MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Genes and Development' source. Sun, 21 Mar 2010 16:44:03 +0100 http://www.medworm.com/index.php?rid=3365511&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F623%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365511 Mon, 15 Mar 2010 14:01:30 +0100 3365511 http://www.medworm.com/index.php?rid=3365510&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F613%3Frss%3D1 Human chromosome end-capping and telomerase regulation require POT1 (Protection of Telomeres 1) and TPP1 proteins, which bind to the 3' ssDNA extension of human telomeres. POT1–TPP1 binding to telomeric DNA activates telomerase repeat addition processivity. We now provide evidence that this POT1–TPP1 activation requires specific interactions with telomerase, rather than it being a DNA substrate-specific effect. First, telomerase from the fish medaka, which extends the same telomeric DNA primer as human telomerase, was not activated by human POT1–TPP1. Second, mutation of a conserved glycine, Gly100 in the TEN (telomerase essential N-terminal) domain of TERT, abolished the enhancement of telomerase processivity by POT1–TPP1, in contrast to other single amino acid mut... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365510 Mon, 15 Mar 2010 14:01:30 +0100 3365510 http://www.medworm.com/index.php?rid=3365509&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F602%3Frss%3D1 Eukaryotic chromosomal DNA replication requires cyclin-dependent kinase (CDK) activity. CDK phosphorylates two yeast replication proteins, Sld3 and Sld2, both of which bind to Dpb11 when phosphorylated. These phosphorylation-dependent interactions are essential and are the minimal requirements for CDK-dependent activation of DNA replication. However, how these interactions activate DNA replication has not been elucidated. Here, we show that CDK promotes the formation of a newly identified fragile complex, the preloading complex (pre-LC) containing DNA polymerase (Pol ), GINS, Sld2, and Dpb11. Formation of the pre-LC requires phosphorylation of Sld2 by CDK, but is independent of DNA replication, protein association with replication origins, and Dbf4-dependent Cdc7 kinase, which is also esse... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365509 Mon, 15 Mar 2010 14:01:30 +0100 3365509 http://www.medworm.com/index.php?rid=3365508&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F590%3Frss%3D1 Timely acquisition of cell fates and the elaborate control of growth in numerous organs depend on Notch signaling. Upon ligand binding, the core transcription factor RBP-J activates transcription of Notch target genes. In the absence of signaling, RBP-J switches off target gene expression, assuring the tight spatiotemporal control of the response by a mechanism incompletely understood. Here we show that the histone demethylase KDM5A is an integral, conserved component of Notch/RBP-J gene silencing. Methylation of histone H3 Lys 4 is dynamically erased and re-established at RBP-J sites upon inhibition and reactivation of Notch signaling. KDM5A interacts physically with RBP-J; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses. (So... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365508 Mon, 15 Mar 2010 14:01:30 +0100 3365508 http://www.medworm.com/index.php?rid=3365507&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F574%3Frss%3D1 Epigenetic modifications of chromatin play an important role in the regulation of gene expression. KMT4/Dot1 is a conserved histone methyltransferase capable of methylating chromatin on Lys79 of histone H3 (H3K79). Here we report the identification of a multisubunit Dot1 complex (DotCom), which includes several of the mixed lineage leukemia (MLL) partners in leukemia such as ENL, AF9/MLLT3, AF17/MLLT6, and AF10/MLLT10, as well as the known Wnt pathway modifiers TRRAP, Skp1, and β-catenin. We demonstrated that the human DotCom is indeed capable of trimethylating H3K79 and, given the association of β-catenin, Skp1, and TRRAP, we investigated, and found, a role for Dot1 in Wnt/Wingless signaling in an in vivo model system. Knockdown of Dot1 in Drosophila results in decreased express... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365507 Mon, 15 Mar 2010 14:01:30 +0100 3365507 http://www.medworm.com/index.php?rid=3365506&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F561%3Frss%3D1 Human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have the unique abilities of differentiation into any cell type of the organism (pluripotency) and indefinite self-renewal. Here, we show that the Rem2 GTPase, a suppressor of the p53 pathway, is up-regulated in hESCs and, by loss- and gain-of-function studies, that it is a major player in the maintenance of hESC self-renewal and pluripotency. We show that Rem2 mediates the fibroblastic growth factor 2 (FGF2) signaling pathway to maintain proliferation of hESCs. We demonstrate that Rem2 effects are mediated by suppressing the transcriptional activity of p53 and cyclin D1 to maintain survival of hESCs. Importantly, Rem2 does this by preventing protein degradation during DNA damage.... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365506 Mon, 15 Mar 2010 14:01:30 +0100 3365506 http://www.medworm.com/index.php?rid=3365505&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F549%3Frss%3D1 Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and Np73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the Np73 isoform. Mice lacking Np73 (Np73–/– mice) are viable and fertile but display signs of neurodegeneration. Cells from Np73–/– mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in Np73–/– cells, we discovered a completely new role for Np73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that Np73 localizes directly to the site of DNA damage, ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365505 Mon, 15 Mar 2010 14:01:30 +0100 3365505 http://www.medworm.com/index.php?rid=3365504&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F543%3Frss%3D1 Regenerative capacity is progressively lost with age. Here we show that pregnancy markedly improved liver regeneration in aged mice concomitantly with inducing a switch from proliferation-based liver regeneration to a regenerative process mediated by cell growth. We found that the key mediator of this switch was the Akt/mTORC1 pathway; its inhibition blocked hypertrophy, while increasing proliferation. Moreover, pharmacological activation of this pathway sufficed to induce the hypertrophy module, mimicking pregnancy. This treatment dramatically improved hepatic regenerative capacity and survival of old mice. Thus, cell growth-mediated mass reconstitution, which is relatively resistant to the detrimental effects of aging, is employed in a physiological situation and holds potential as a the... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365504 Mon, 15 Mar 2010 14:01:30 +0100 3365504 http://www.medworm.com/index.php?rid=3365503&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F537%3Frss%3D1 Estrogen-related receptor (ERR) and proliferator-activated receptor coactivator-1 (PGC-1) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERR and PGC-1, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERR/PGC-1 complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERR and other factors. Importantly, ablation of Prox1 and ERR have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365503 Mon, 15 Mar 2010 14:01:30 +0100 3365503 http://www.medworm.com/index.php?rid=3365502&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F521%3Frss%3D1 Chromosomal double-strand breaks (DSBs) are considered to be among the most deleterious DNA lesions found in eukaryotic cells due to their propensity to promote genome instability. DSBs occur as a result of exogenous or endogenous DNA damage, and also occur during meiotic recombination. DSBs are often repaired through a process called homologous recombination (HR), which employs the sister chromatid in mitotic cells or the homologous chromosome in meiotic cells, as a template for repair. HR frequently involves the formation and resolution of four-way DNA structures referred to as the Holliday junction (HJ). Despite extensive study, the machinery and mechanisms used to process these structures in eukaryotes have remained poorly understood. Recent work has identified XPG and UvrC/GIY domain-... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365502 Mon, 15 Mar 2010 14:01:30 +0100 3365502 http://www.medworm.com/index.php?rid=3365501&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F6%2F517%3Frss%3D1 Mammalian cells are barraged with endogenous metabolic byproducts and environmental insults that can lead to nearly a million genomic lesions per cell per day. Networks of proteins that repair these lesions are essential for genome maintenance, and a compromise in these pathways propagates mutations that can cause aging and cancer. The p53 tumor suppressor plays a central role in repairing the effects of DNA damage, and has therefore earned the title of "guardian of the genome." In this issue of Genes & Development, Wilhelm and colleagues (pp. 549–560) demonstrate that p73—an older sibling of p53—inhibits pathways that resolve DNA double-strand breaks. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3365501 Mon, 15 Mar 2010 14:01:30 +0100 3365501 http://www.medworm.com/index.php?rid=3317691&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F516%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317691 Mon, 01 Mar 2010 15:01:47 +0100 3317691 http://www.medworm.com/index.php?rid=3317690&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F502%3Frss%3D1 DNA double-strand breaks (DSBs) are a threat to cell survival and genome integrity. In addition to canonical DNA repair systems, DSBs can be converted to telomeres by telomerase. This process, herein termed telomere healing, endangers genome stability, since it usually results in chromosome arm loss. Therefore, cells possess mechanisms that prevent the untimely action of telomerase on DSBs. Here we report that Mec1, the ATR ortholog, couples the detection of DNA ends with the inhibition of telomerase. Mec1 inhibits telomere healing by phosphorylating Cdc13 on its S306 residue, a phosphorylation event that suppresses Cdc13 accumulation at DSBs. Conversely, telomere addition at accidental breaks is promoted by Pph3, the yeast protein phosphatase 4 (PP4). Pph3 is itself modulated by Rrd1, an ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317690 Mon, 01 Mar 2010 15:01:47 +0100 3317690 http://www.medworm.com/index.php?rid=3317689&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F491%3Frss%3D1 Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1 and HIF-2. Previous studies have revealed that both HIF- proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF- isoforms can be differentially activated: HIF-1 is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2 is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF- isoform-spe... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317689 Mon, 01 Mar 2010 15:01:47 +0100 3317689 http://www.medworm.com/index.php?rid=3317688&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F478%3Frss%3D1 Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid di... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317688 Mon, 01 Mar 2010 15:01:47 +0100 3317688 http://www.medworm.com/index.php?rid=3317687&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F470%3Frss%3D1 β-TrCP, the substrate recognition subunit of a Skp1–Cul1–F-box (SCF) ubiquitin ligase, is ubiquitously expressed from two distinct paralogs, targeting many regulatory proteins for proteasomal degradation. We generated inducible β-TrCP hypomorphic mice and found that they are surprisingly healthy, yet have a severe testicular defect. We show that the two β-TrCP paralogs have a nonredundant role in spermatogenesis. The testicular defect is tightly associated with cell adhesion failure within the seminiferous tubules and is fully reversible upon β-TrCP restoration. Remarkably, testicular depletion of a single β-TrCP substrate, Snail1, rescued the adhesion defect and restored spermatogenesis. Our studies highlight an unexpected functional reserve of this ce... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317687 Mon, 01 Mar 2010 15:01:47 +0100 3317687 http://www.medworm.com/index.php?rid=3317686&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F455%3Frss%3D1 Histone deacetylases (HDACs) regulate gene expression by deacetylating histones and also modulate the acetylation of a number of nonhistone proteins, thus impinging on various cellular processes. Here, we analyzed the major class I enzymes HDAC1 and HDAC2 in primary mouse fibroblasts and in the B-cell lineage. Fibroblasts lacking both enzymes fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with up-regulation of the CDK inhibitors p21WAF1/CIP1 and p57Kip2 and of the corresponding mRNAs. This regulation is direct, as in wild-type cells HDAC1 and HDAC2 are bound to the promoter regions of the p21 and p57 genes. Furthermore, analysis of the transcriptome and of histone modifications in mutant cells demonstrated that HDAC1 and HDAC2 have o... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317686 Mon, 01 Mar 2010 15:01:47 +0100 3317686 http://www.medworm.com/index.php?rid=3317685&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F443%3Frss%3D1 Transposable elements are common in genomes and must be controlled. Many organisms use DNA methylation to silence such selfish DNA, but the mechanisms that restrict the methylation to appropriate regions are largely unknown. We identified a JmjC domain protein in Neurospora, DNA METHYLATION MODULATOR-1 (DMM-1), that prevents aberrant spreading of DNA and histone H3K9 methylation from inactivated transposons into nearby genes. Mutation of a conserved residue within the JmjC Fe(II)-binding site abolished dmm-1 function, as did mutations in conserved cysteine-rich domains. Mutants defective only in dmm-1 mutants grow poorly, but growth is restored by reduction or elimination of DNA methylation using the drug 5-azacytosine or by mutation of the DNA methyltransferase gene dim-2. DMM-1 relies on... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317685 Mon, 01 Mar 2010 15:01:47 +0100 3317685 http://www.medworm.com/index.php?rid=3317684&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F438%3Frss%3D1 Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletions, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, most of the mRNA produced from SMN2 pre-mRNA is exon 7-skipped (~80%), resulting in a highly unstable and almost undetectable protein (SMN7). We show that this splicing defect creates a potent degradation signal (degron; SMN7-DEG) at SMN7's C-terminal 15 amino acids. The S270A mutation inactivates SMN7-DEG, generating a stable SMN7 that rescues viability of SMN-deleted cells. These findings explain a key aspect of the SMA disease mechanism, and suggest new treatment approaches based on interference with SMN7-DEG activity. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317684 Mon, 01 Mar 2010 15:01:47 +0100 3317684 http://www.medworm.com/index.php?rid=3317683&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F432%3Frss%3D1 Methylation of histone H3 Lys 9 and Lys 27 (H3K9 and H3K27) is associated with transcriptional silencing. Here we show that KDM7, a JmjC domain-containing protein, catalyzes demethylation of both mono- or dimethylated H3K9 and H3K27. Inhibition of KDM7 orthologs in zebrafish resulted in developmental brain defects. KDM7 interacts with the follistatin gene locus, and KDM7 depletion in mammalian neuronal cells suppressed follistatin gene transcription in association with increased levels of dimethylated H3K9 and H3K27. Our findings identify KDM7 as a dual demethylase for H3K9 and H3K27 that functions as an eraser of silencing marks on chromatin during brain development. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317683 Mon, 01 Mar 2010 15:01:47 +0100 3317683 http://www.medworm.com/index.php?rid=3317682&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F5%2F423%3Frss%3D1 The revolution in DNA sequencing technologies has now made it feasible to determine the genome sequences of many individuals; i.e., "personal genomes." Genome sequences of cells and tissues from both normal and disease states have been determined. Using current approaches, whole human genome sequences are not typically assembled and determined de novo, but, instead, variations relative to a reference sequence are identified. We discuss the current state of personal genome sequencing, the main steps involved in determining a genome sequence (i.e., identifying single-nucleotide polymorphisms [SNPs] and structural variations [SVs], assembling new sequences, and phasing haplotypes), and the challenges and performance metrics for evaluating the accuracy of the reconstruction. Finally, we consid... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3317682 Mon, 01 Mar 2010 15:01:47 +0100 3317682 http://www.medworm.com/index.php?rid=3275050&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F411%3Frss%3D1 How proteins catalyze morphogenesis is an outstanding question in developmental biology. In bacteria, morphogenesis is intimately linked to remodeling the cell wall exoskeleton. Here, we investigate the mechanisms by which the mother cell engulfs the prospective spore during sporulation in Bacillus subtilis. A membrane-anchored protein complex containing two cell wall hydrolases plays a central role in this morphological process. We demonstrate that one of the proteins (SpoIIP) has both amidase and endopeptidase activities, such that it removes the stem peptides from the cell wall and cleaves the cross-links between them. We further show that the other protein (SpoIID) is the founding member of a new family of lytic transglycosylases that degrades the glycan strands of the peptidoglycan in... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275050 Tue, 16 Feb 2010 15:01:22 +0100 3275050 http://www.medworm.com/index.php?rid=3275049&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F396%3Frss%3D1 Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275049 Tue, 16 Feb 2010 15:01:22 +0100 3275049 http://www.medworm.com/index.php?rid=3275048&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F381%3Frss%3D1 We report that selective synthetic agonists induce SUMOylation-dependent recruitment of either LRH-1 or LXR to hepatic APR promoters and prevent the clearance of the N-CoR corepressor complex upon cytokine stimulation. Investigations of the APR in vivo, using LXR knockout mice, indicate that the anti-inflammatory actions of LXR agonists are triggered selectively by the LXRβ subtype. We further find that hepatic APR responses in small ubiquitin-like modifier-1 (SUMO-1) knockout mice are increased, which is due in part to diminished LRH-1 action at APR promoters. Finally, we provide evidence that the metabolically important coregulator GPS2 functions as a hitherto unrecognized transrepression mediator of interactions between SUMOylated nuclear receptors and the N-CoR corepressor complex... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275048 Tue, 16 Feb 2010 15:01:22 +0100 3275048 http://www.medworm.com/index.php?rid=3275047&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F368%3Frss%3D1 The Polycomb group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the Polycomb-Repressive Complex 2 (PRC2) including the histone H3 Lys 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We found that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in corecruitment of PRC2 with resultant increased levels of di- and trimethylation of H3K27 (H3K27me2/3). Jarid2 colocalizes with Ezh2 and MTF2, a homolog of Drosophila Pcl, at endogenous genes in embryonic stem (ES) cells. Jarid2 can bind DNA a... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275047 Tue, 16 Feb 2010 15:01:22 +0100 3275047 http://www.medworm.com/index.php?rid=3275046&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F358%3Frss%3D1 We report here in the Drosophila model two different mechanisms by which the circadian repressor PERIOD (PER) inhibits CLOCK/CYCLE (CLK/CYC)-mediated transcription. First, PER is recruited to circadian promoters, which leads to the nighttime decrease of CLK/CYC activity. This decrease is proportional to PER levels on DNA, and PER recruitment probably occurs via CLK. Then CLK is released from DNA and sequestered in a strong, ~1:1 PER–CLK off-DNA complex. The data indicate that the PER levels bound to CLK change dynamically and are important for repression, first on-DNA and then off-DNA. They also suggest that these mechanisms occur upstream of post-translational events, and that elements of this two-step mechanism likely apply to mammals. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275046 Tue, 16 Feb 2010 15:01:22 +0100 3275046 http://www.medworm.com/index.php?rid=3275045&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F345%3Frss%3D1 Mammalian circadian clocks provide a temporal framework to synchronize biological functions. To obtain robust rhythms with a periodicity of about a day, these clocks use molecular oscillators consisting of two interlocked feedback loops. The core loop generates rhythms by transcriptional repression via the Period (PER) and Cryptochrome (CRY) proteins, whereas the stabilizing loop establishes roughly antiphasic rhythms via nuclear receptors. Nuclear receptors also govern many pathways that affect metabolism and physiology. Here we show that the core loop component PER2 can coordinate circadian output with the circadian oscillator. PER2 interacts with nuclear receptors including PPAR and REV-ERB and serves as a coregulator of nuclear receptor-mediated transcription. Consequently, PER2 is rhy... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275045 Tue, 16 Feb 2010 15:01:22 +0100 3275045 http://www.medworm.com/index.php?rid=3275044&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F339%3Frss%3D1 Heat-stable nucleoid structuring protein (H-NS) is an abundant prokaryotic protein that plays important roles in organizing chromosomal DNA and gene silencing. Two controversial binding modes were identified. H-NS binding stimulating DNA bridging has become the accepted mechanism, whereas H-NS binding causing DNA stiffening has been largely ignored. Here, we report that both modes exist, and that changes in divalent cations drive a switch between them. The stiffening form is present under physiological conditions, and directly responds to pH and temperature in vitro. Our findings have broad implications and require a reinterpretation of the mechanism by which H-NS regulates genes. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275044 Tue, 16 Feb 2010 15:01:22 +0100 3275044 http://www.medworm.com/index.php?rid=3275043&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F333%3Frss%3D1 A balanced deoxyribonucleotide (dNTP) supply is essential for DNA repair. Here, we found that ribonucleotide reductase (RNR) subunits RRM1 and RRM2 accumulated very rapidly at damage sites. RRM1 bound physically to Tip60. Chromatin immunoprecipitation analyses of cells with an I-SceI cassette revealed that RRM1 bound to a damage site in a Tip60-dependent manner. Active RRM1 mutants lacking Tip60 binding failed to rescue an impaired DNA repair in RRM1-depleted G1-phase cells. Inhibition of RNR recruitment by an RRM1 C-terminal fragment sensitized cells to DNA damage. We propose that Tip60-dependent recruitment of RNR plays an essential role in dNTP supply for DNA repair. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275043 Tue, 16 Feb 2010 15:01:22 +0100 3275043 http://www.medworm.com/index.php?rid=3275042&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F4%2F327%3Frss%3D1 Trimethylation of histone H3 on Lys 27 (H3K27me3) is key for cell fate regulation. The H3K27me3 demethylase UTX functions in development and tumor suppression with undefined mechanisms. Here, genome-wide chromatin occupancy analysis of UTX and associated histone modifications reveals distinct classes of UTX target genes, including genes encoding Retinoblastoma (RB)-binding proteins. UTX removes H3K27me3 and maintains expression of several RB-binding proteins, enabling cell cycle arrest. Genetic interactions in mammalian cells and Caenorhabditis elegans show that UTX regulates cell fates via RB-dependent pathways. Thus, UTX defines an evolutionarily conserved mechanism to enable coordinate transcription of a RB network in cell fate control. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3275042 Tue, 16 Feb 2010 15:01:22 +0100 3275042 http://www.medworm.com/index.php?rid=3226804&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F312%3Frss%3D1 In embryonic stem (ES) cells, a well-characterized transcriptional network promotes pluripotency and represses gene expression required for differentiation. In comparison, the transcriptional networks that promote differentiation of ES cells and the blastocyst inner cell mass are poorly understood. Here, we show that Sox17 is a transcriptional regulator of differentiation in these pluripotent cells. ES cells deficient in Sox17 fail to differentiate into extraembryonic cell types and maintain expression of pluripotency-associated transcription factors, including Oct4, Nanog, and Sox2. In contrast, forced expression of Sox17 down-regulates ES cell-associated gene expression and directly activates genes functioning in differentiation toward an extraembryonic endoderm cell fate. We show these ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226804 Mon, 01 Feb 2010 15:02:48 +0100 3226804 http://www.medworm.com/index.php?rid=3226803&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F301%3Frss%3D1 In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 (Zfp191), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein–protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function.... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226803 Mon, 01 Feb 2010 15:02:48 +0100 3226803 http://www.medworm.com/index.php?rid=3226802&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F290%3Frss%3D1 The Hippo signaling pathway controls cell growth, proliferation, and apoptosis by regulating the expression of target genes that execute these processes. Acting downstream from this pathway is the YAP transcriptional coactivator, whose biological function is mediated by the conserved TEAD family transcription factors. The interaction of YAP with TEADs is critical to regulate Hippo pathway-responsive genes. Here, we describe the crystal structure of the YAP-interacting C-terminal domain of TEAD4 in complex with the TEAD-interacting N-terminal domain of YAP. The structure reveals that the N-terminal region of YAP is folded into two short helices with an extended loop containing the PXXP motif in between, while the C-terminal domain of TEAD4 has an immunoglobulin-like fold. YAP interacts with... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226802 Mon, 01 Feb 2010 15:02:48 +0100 3226802 http://www.medworm.com/index.php?rid=3226801&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F277%3Frss%3D1 One of the complexes formed by the hematopoietic transcription factor Gata1 is a complex with the Ldb1 (LIM domain-binding protein 1) and Tal1 proteins. It is known to be important for the development and differentiation of the erythroid cell lineage and is thought to be implicated in long-range interactions. Here, the dynamics of the composition of the complex—in particular, the binding of the negative regulators Eto2 and Mtgr1—are studied, in the context of their genome-wide targets. This shows that the complex acts almost exclusively as an activator, binding a very specific combination of sequences, with a positioning relative to transcription start site, depending on the type of the core promoter. The activation is accompanied by a net decrease in the relative binding of Et... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226801 Mon, 01 Feb 2010 15:02:48 +0100 3226801 http://www.medworm.com/index.php?rid=3226800&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F265%3Frss%3D1 Polycomb complexes establish chromatin modifications for maintaining gene repression and are essential for embryonic development in mice. Here we use pluripotent embryonic stem (ES) cells to demonstrate an unexpected redundancy between Polycomb-repressive complex 1 (PRC1) and PRC2 during the formation of differentiated cells. ES cells lacking the function of either PRC1 or PRC2 can differentiate into cells of the three germ layers, whereas simultaneous loss of PRC1 and PRC2 abrogates differentiation. On the molecular level, the differentiation defect is caused by the derepression of a set of genes that is redundantly repressed by PRC1 and PRC2 in ES cells. Furthermore, we find that genomic repeats are Polycomb targets and show that, in the absence of Polycomb complexes, endogenous murine l... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226800 Mon, 01 Feb 2010 15:02:48 +0100 3226800 http://www.medworm.com/index.php?rid=3226799&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F256%3Frss%3D1 The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic–pituitary–thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic–pituitary–thyroid axis represents an important target of metabolic signaling by JNK1. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226799 Mon, 01 Feb 2010 15:02:48 +0100 3226799 http://www.medworm.com/index.php?rid=3226798&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F241%3Frss%3D1 Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors, and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis, and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin-4 (IL-4)... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226798 Mon, 01 Feb 2010 15:02:48 +0100 3226798 http://www.medworm.com/index.php?rid=3226797&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F235%3Frss%3D1 The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50–171)–TEAD1 (residues 194–411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86–100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP–TEAD interaction, and provides a basis for pharmacological intervention of YAP–TEAD hyperactivation in human dise... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226797 Mon, 01 Feb 2010 15:02:48 +0100 3226797 http://www.medworm.com/index.php?rid=3226796&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F229%3Frss%3D1 During development, multiple cell types within a tissue often arise from a common pool of progenitor cells (PCs). PCs typically expand in number, while simultaneously producing post-mitotic cells (PMCs). This balance is partly regulated by transcription factors that are expressed within PCs, such as the basic helix–loop–helix (bHLH) gene mouse atonal homolog 7 (Math5), which is expressed in retinal PCs. Here we report that alternative splicing (AS) of Math5 serves as another layer of regulation of Math5 activity. Specifically, Math5, a single exon gene, is alternatively spliced such that the major isoform lacks the entire coding sequence. Similarly, neurogenin 3 (Ngn3), a Math5 paralog expressed in pancreatic PCs, is also alternatively spliced such that the major isoform fails ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226796 Mon, 01 Feb 2010 15:02:48 +0100 3226796 http://www.medworm.com/index.php?rid=3226795&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F3%2F219%3Frss%3D1 Organisms that reproduce sexually must reduce their chromosome number by half during meiosis to generate haploid gametes. To achieve this reduction in ploidy, organisms must devise strategies to couple sister chromatids so that they stay together during the first meiotic division (when homologous chromosomes separate) and then segregate away from one another during the second division. Here we review recent findings that shed light on how Caenorhabditis elegans, an organism with holocentric chromosomes, deals with these challenges of meiosis by differentiating distinct chromosomal subdomains and remodeling chromosome structure during prophase. Furthermore, we discuss how features of chromosome organization established during prophase affect later chromosome behavior during the meiotic divi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3226795 Mon, 01 Feb 2010 15:02:48 +0100 3226795 http://www.medworm.com/index.php?rid=3174702&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F206%3Frss%3D1 Neuronal differentiation is regulated by proneural genes that promote neurogenesis and inhibitory mechanisms that maintain progenitors. This raises the question of how the up-regulation of proneural genes required to initiate neurogenesis occurs in the presence of such inhibition. We carried out loss and gain of gene function, an interaction screen for binding partners, and biochemical analyses to uncover the regulation, developmental role, and mechanism of action of a ubiquitination adaptor protein, Btbd6a (BTB domain containing 6a). We find that the proneural gene neurog1 up-regulates btbd6a, which in turn is required for up-regulation of neurog1. Btbd6a is an adaptor for the Cul3 ubiquitin ligase complex, and we find that it binds to the transcriptional repressor Plzf (promyelocytic leu... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174702 Fri, 15 Jan 2010 15:02:11 +0100 3174702 http://www.medworm.com/index.php?rid=3174701&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F195%3Frss%3D1 Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs b... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174701 Fri, 15 Jan 2010 15:02:11 +0100 3174701 http://www.medworm.com/index.php?rid=3174700&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F183%3Frss%3D1 Eukaryotes have numerous checkpoint pathways to protect genome fidelity during normal cell division and in response to DNA damage. Through a screen for G2/M checkpoint regulators in zebrafish, we identified ticrr (for TopBP1-interacting, checkpoint, and replication regulator), a previously uncharacterized gene that is required to prevent mitotic entry after treatment with ionizing radiation. Ticrr deficiency is embryonic-lethal in the absence of exogenous DNA damage because it is essential for normal cell cycle progression. Specifically, the loss of ticrr impairs DNA replication and disrupts the S/M checkpoint, leading to premature mitotic entry and mitotic catastrophe. We show that the human TICRR ortholog associates with TopBP1, a known checkpoint protein and a core component of the DNA ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174700 Fri, 15 Jan 2010 15:02:11 +0100 3174700 http://www.medworm.com/index.php?rid=3174699&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F171%3Frss%3D1 Retinoic acid receptor- (RAR) is a known estrogen target gene in breast cancer cells. The consequence of RAR induction by estrogen was previously unknown. We now show that RAR is required for efficient estrogen receptor- (ER)-mediated transcription and cell proliferation. RAR can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR that is independent of its classic role. We show, on a genome-wide scale, that RAR and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen—an interaction that is promoted by the estrogen–ER induction of RAR. These findings implicate RAR as an essential comp... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174699 Fri, 15 Jan 2010 15:02:11 +0100 3174699 http://www.medworm.com/index.php?rid=3174698&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F159%3Frss%3D1 Chromatin reorganization is essential for transcriptional control by sequence-specific transcription factors. However, the molecular link between transcriptional control and chromatin reconfiguration remains unclear. By colocalization of the nuclear ecdysone receptor (EcR) on the ecdysone-induced puff in the salivary gland, Drosophila DEK (dDEK) was genetically identified as a coactivator of EcR in both insect cells and intact flies. Biochemical purification and characterization of the complexes containing fly and human DEKs revealed that DEKs serve as histone chaperones via phosphorylation by forming complexes with casein kinase 2. Consistent with the preferential association of the DEK complex with histones enriched in active epigenetic marks, dDEK facilitated H3.3 assembly during puff f... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174698 Fri, 15 Jan 2010 15:02:11 +0100 3174698 http://www.medworm.com/index.php?rid=3174697&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F148%3Frss%3D1 ZBP1 (zipcode-binding protein 1) was originally discovered as a trans-acting factor for the "zipcode" in the 3' untranslated region (UTR) of the β-actin mRNA that is important for its localization and translational regulation. Subsequently, ZBP1 has been found to be a multifunctional regulator of RNA metabolism that controls aspects of localization, stability, and translation for many mRNAs. To reveal how ZBP1 recognizes its RNA targets, we biochemically characterized the interaction between ZBP1 and the β-actin zipcode. The third and fourth KH (hnRNP K homology) domains of ZBP1 specifically recognize a bipartite RNA element located within the first 28 nucleotides of the zipcode. The spacing between the RNA sequences is consistent with the structure of IMP1 KH34, the human orthol... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174697 Fri, 15 Jan 2010 15:02:11 +0100 3174697 http://www.medworm.com/index.php?rid=3174696&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F135%3Frss%3D1 p53 target promoters are structurally diverse and display pronounced differences in RNA polymerase II (RNAP II) occupancy even in unstressed cells, with higher levels observed on cell cycle arrest genes (p21) compared with apoptotic genes (Fas/APO1). This occupancy correlates well with their ability to undergo rapid or delayed stress induction. To understand the basis for such distinct temporal assembly of transcription complexes, we examined the role of core promoter structures in this process. We find that the p21 core promoter directs rapid, TATA box-dependent assembly of RNAP II preinitiation complexes (PICs), but permits few rounds of RNAP II reinitiation. In contrast, PIC formation at the Fas/APO1 core promoter is very inefficient but supports multiple rounds of transcription. We def... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174696 Fri, 15 Jan 2010 15:02:11 +0100 3174696 http://www.medworm.com/index.php?rid=3174695&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F129%3Frss%3D1 Cytoplasmic polyadenylation is a widespread mechanism to regulate mRNA translation that requires two sequences in the 3' untranslated region (UTR) of vertebrate substrates: the polyadenylation hexanucleotide, and the cytoplasmic polyadenylation element (CPE). Using a cell-free Drosophila system, we show that these signals are not relevant for Toll polyadenylation but, instead, a "polyadenylation region" (PR) is necessary. Competition experiments indicate that PR-mediated polyadenylation is required for viability and is mechanistically distinct from the CPE/hexanucleotide-mediated process. These data indicate that Toll mRNA is polyadenylated by a noncanonical mechanism, and suggest that a novel machinery functions for cytoplasmic polyadenylation during Drosophila embryogenesis. (Source: Gen... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174695 Fri, 15 Jan 2010 15:02:11 +0100 3174695 http://www.medworm.com/index.php?rid=3174694&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F123%3Frss%3D1 The ultraviolet (UV)-induced (6–4) pyrimidine–pyrimidone photoproduct [(6–4) PP] confers a large structural distortion in DNA. Here we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in promoting replication through a (6–4) TT photoproduct carried on a duplex plasmid where bidirectional replication initiates from an origin of replication. We show that TLS contributes to a large fraction of lesion bypass and that it is mostly error-free. We find that, whereas Pol and Pol provide alternate pathways for mutagenic TLS, surprisingly, Pol functions independently of these Pols and in a predominantly error-free manner. We verify and extend these observations in mouse cells and conclude that, in human cells, TLS during replication can b... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174694 Fri, 15 Jan 2010 15:02:11 +0100 3174694 http://www.medworm.com/index.php?rid=3174693&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F115%3Frss%3D1 A recent explosion of work surrounds the interactions between Sir3p (Silent Information Regulator 3) and chromatin. We review here the Sir3p functions related to its role in silencing in Saccharomyces cerevisiae. This unusual protein, which is absolutely required for silencing, is distantly related to the highly conserved replication initiator Orc1p, but is itself phylogenetically limited to "post-genome-duplicated" budding yeasts. Several recent studies revise earlier models for Sir3p action. Specifically, the N-terminal bromo-adjacent homology (BAH) domain plays a now well-defined role in silencing, and a picture is emerging in which both termini of Sir3p bind two locations on the nucleosome: (1) the loss of ribosomal DNA silencing (LRS) surface in the nucleosome core, and (2) the N-term... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174693 Fri, 15 Jan 2010 15:02:11 +0100 3174693 http://www.medworm.com/index.php?rid=3174692&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F2%2F111%3Frss%3D1 p53 is a pleiotropic transcription factor driving a flexible transcriptional program that mediates disparate cellular responses to stress, including cell cycle arrest and apoptosis. The mechanisms by which p53 differentially regulates its diverse target genes remain poorly understood. In this issue of Genes & Development, Morachis and colleagues (pp. 135–147) demonstrate the critical role of core promoter elements at p53 target loci, in that they dictate differential RNA polymerase II recruitment and activity in a p53-autonomous fashion. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3174692 Fri, 15 Jan 2010 15:02:11 +0100 3174692 http://www.medworm.com/index.php?rid=3138538&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F97%3Frss%3D1 eIF1A is the eukaryotic ortholog of bacterial translation initiation factor IF1, but contains a helical domain and long unstructured N-terminal tail (NTT) and C-terminal tail (CTT) absent in IF1. Here, we identify elements in these accessory regions of eIF1A with dual functions in binding methionyl initiator tRNA (Met-tRNAiMet) to the ribosome and in selecting AUG codons. A pair of repeats in the eIF1A CTT, dubbed Scanning Enhancer 1 (SE1) and SE2, was found to stimulate recruitment of Met-tRNAiMet in the ternary complex (TC) with eIF2·GTP and also to block initiation at UUG codons. In contrast, the NTT and segments of the helical domain are required for the elevated UUG initiation occurring in SE mutants, and both regions also impede TC recruitment. Remarkably, mutations in these l... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138538 Mon, 04 Jan 2010 15:02:57 +0100 3138538 http://www.medworm.com/index.php?rid=3138537&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F86%3Frss%3D1 Metazoan E(y)2/ENY2 is a multifunctional protein important for transcription activation and mRNA export, being a component of SAGA/TFTC and the mRNA export complex AMEX. Here, we show that ENY2 in Drosophila is also stably associated with THO, the complex involved in mRNP biogenesis. The ENY2–THO complex is required for normal Drosophila development, functioning independently on SAGA and AMEX. ENY2 and THO arrive on the transcribed region of the hsp70 gene after its activation, and ENY2 plays an important role in THO recruitment. ENY2 and THO show no direct association with elongating RNA polymerase II. Recruitment of ENY2 and THO occurs by their loading onto nascent mRNA, apparently immediately after its synthesis, while the AMEX component Xmas-2 is loaded onto mRNA at a later stage... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138537 Mon, 04 Jan 2010 15:02:57 +0100 3138537 http://www.medworm.com/index.php?rid=3138536&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F72%3Frss%3D1 The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14–3–3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1/ in a phosphodegron. The phosphorylated phosphodegron then recruits the SCFβ-TRCP E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138536 Mon, 04 Jan 2010 15:02:57 +0100 3138536 http://www.medworm.com/index.php?rid=3138535&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F57%3Frss%3D1 Although the transporter-like protein Patched (Ptc) is genetically implicated in reception of the extracellular Hedgehog (Hh) protein signal, a clear definition of the Hh receptor is complicated by the existence of additional Hh-binding proteins and, in Drosophila, by the lack of physical evidence for direct binding of Hh to Ptc. Here we show that activity of Ihog (Interference hedgehog), or of its close relative Boi (Brother of Ihog), is absolutely required for Hh biological response and for sequestration of the Hh protein to limit long-range signaling. We demonstrate that Ihog interacts directly with Ptc, is required for presentation of Ptc on the cell surface, and that Ihog and Ptc are both required for high-affinity Hh binding. On the basis of their joint roles in ligand binding, signa... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138535 Mon, 04 Jan 2010 15:02:57 +0100 3138535 http://www.medworm.com/index.php?rid=3138534&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F45%3Frss%3D1 Neural stem cells (NSCs) have great potential for self-renewal, which must be tightly regulated to generate appropriate cell numbers during development and to prevent tumor formation. The Ras–MAPK–ERK pathway affects mitogen-stimulated proliferation, and negative regulators are likely to be important for keeping self-renewal in check. Sprouty-related protein with an EVH1 domain (Spred1) is a recently discovered negative Ras–MAPK–ERK regulator linked to a neurofibromatosis 1 (NF-1)-like human syndrome; however, its role in CNS development has not been explored. We show that Spred1 is highly enriched in CNS germinal zones during neurogenesis. Spred1 knockdown increases NSC self-renewal and progenitor proliferation cell-autonomously, and overexpression causes premature... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138534 Mon, 04 Jan 2010 15:02:57 +0100 3138534 http://www.medworm.com/index.php?rid=3138533&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F33%3Frss%3D1 This study provides empirical evidence for selfish DNA promoting host sexual reproduction by mediating mating type switch. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138533 Mon, 04 Jan 2010 15:02:57 +0100 3138533 http://www.medworm.com/index.php?rid=3138532&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F21%3Frss%3D1 MacroH2A1 is a histone variant that is enriched on the inactive X chromosome (Xi) in mammals and is postulated to play an important, but unknown, role in the repression of gene expression. Here we show that, although macroH2A1 marks repressed autosomal chromatin, it positively regulates transcription when located in the transcribed regions of a subset of its target genes. We used chromatin immunoprecipitation (ChIP) coupled with tiling microarrays (ChIP–chip) to determine the genomic localization of macroH2A1 in IMR90 human primary lung fibroblasts and MCF-7 breast cancer cells. The patterns of macroH2A1 deposition are largely similar across the autosomes of both cell lines. Our studies revealed a genomic localization pattern unique among histone variants; namely, the occupation by m... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138532 Mon, 04 Jan 2010 15:02:57 +0100 3138532 http://www.medworm.com/index.php?rid=3138531&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F15%3Frss%3D1 We report that mice deficient for the CCAAT/enhancer-binding protein β (C/EBPβ) uORF initiation codon fail to initiate translation of the autoantagonistic LIP (liver inhibitory protein) C/EBPβ isoform. C/EBPβuORF mice show hyperactivation of acute-phase response genes, persistent repression of E2F-regulated genes, delayed and blunted S-phase entry of hepatocytes after partial hepatectomy, and impaired osteoclast differentiation. These data and the widespread prevalence of uORFs in mammalian transcriptomes suggest a comprehensive role of uORF-regulated translation in (patho)physiology. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138531 Mon, 04 Jan 2010 15:02:57 +0100 3138531 http://www.medworm.com/index.php?rid=3138530&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F10%3Frss%3D1 Programmed DNA rearrangements are critical for the development of many organisms and, intriguingly, can be catalyzed by domesticated mobile genetic elements. In this issue of Genes & Development, Barsoum and colleagues (pp. 33–44) demonstrate that, in the budding yeast Kluyveromyces lactis, a DNA rearrangement associated with mating type switching requires a domesticated transposase and occurs through a mechanism distinct from that in the related yeast, Saccharomyces cerevisiae. Thus, mechanisms for mating type switching have evolved multiple times, indicating the relative ease with which mobile genetic elements can be captured. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138530 Mon, 04 Jan 2010 15:02:57 +0100 3138530 http://www.medworm.com/index.php?rid=3138529&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F5%3Frss%3D1 Genome rearrangements are often associated with genome instability observed in cancer and other pathological disorders. Different types of repeat elements are common in genomes and are prone to instability. S-phase checkpoints, recombination, and telomere maintenance pathways have been implicated in suppressing chromosome rearrangements, but little is known about the molecular mechanisms and the chromosome intermediates generating such genome-wide instability. In the December 15, 2009, issue of Genes & Development, two studies by Paek and colleagues (2861–2875) and Mizuno and colleagues (pp. 2876–2886), demonstrate that nearby inverted repeats in budding and fission yeasts recombine spontaneously and frequently to form dicentric and acentric chromosomes. The recombination m... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138529 Mon, 04 Jan 2010 15:02:57 +0100 3138529 http://www.medworm.com/index.php?rid=3138528&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F24%2F1%2F1%3Frss%3D1 The miR-17-92 gene cluster, with its six different mature microRNAs (miRNAs), has an established oncogenic function. However, the oncogenic contribution of each individual miRNA in the cluster has not been assigned. Two studies published in the December 15, 2009, issue of Genes & Development by Mu and colleagues (pp. 2806–2811) and Olive and colleagues (pp. 2839–2849) dissected the miR-17-92 cluster to its individual miRNA components and identified their relative contributions to oncogenic transformation in mouse model systems. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3138528 Mon, 04 Jan 2010 15:02:57 +0100 3138528 http://www.medworm.com/index.php?rid=3088315&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2915%3Frss%3D1 Mechanisms of telomere replication remain poorly defined. It has been suggested that G-rich telomeric strand replication by lagging mechanisms requires, in a stochastic way, the WRN protein. Here we show that this requirement is more systematic than previously thought. Our data are compatible with a situation in which, in the absence of WRN, DNA synthesis at replication forks is uncoupled, thus allowing replication to continue on the C strand, while single G strands accumulate. We also show that in cells in which both WRN and POT1 are limiting, both G- and C-rich telomeric strands shorten, suggesting a complete replication block. Under this particular condition, expression of a fragment spanning the two POT1-OB (oligonucleotide-binding) fold domains is able to restore C (but not G) strand ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088315 Tue, 15 Dec 2009 15:02:55 +0100 3088315 http://www.medworm.com/index.php?rid=3088314&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2900%3Frss%3D1 In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N–Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088314 Tue, 15 Dec 2009 15:02:55 +0100 3088314 http://www.medworm.com/index.php?rid=3088313&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2887%3Frss%3D1 The kinetochore is a macromolecular complex that controls chromosome segregation and cell cycle progression. When sister kinetochores make bioriented attachments to microtubules from opposite poles, the spindle checkpoint is silenced. Biorientation and the spindle checkpoint are regulated by a balance between the Ipl1/Aurora B protein kinase and the opposing activity of protein phosphatase I (PP1). However, little is known about the regulation of PP1 localization and activity at the kinetochore. Here, we developed a method to purify centromere-bound kinetochores and used quantitative proteomics to identify the Fin1 protein as a PP1 regulatory subunit. The Fin1/PP1 complex is regulated by phosphorylation and 14–3–3 protein binding. When Fin1 is mislocalized, bipolar spindles fai... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088313 Tue, 15 Dec 2009 15:02:55 +0100 3088313 http://www.medworm.com/index.php?rid=3088312&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2876%3Frss%3D1 Gene amplification plays important roles in the progression of cancer and contributes to acquired drug resistance during treatment. Amplification can initiate via dicentric palindromic chromosome production and subsequent breakage–fusion–bridge cycles. Here we show that, in fission yeast, acentric and dicentric palindromic chromosomes form by homologous recombination protein-dependent fusion of nearby inverted repeats, and that these fusions occur frequently when replication forks arrest within the inverted repeats. Genetic and molecular analyses suggest that these acentric and dicentric palindromic chromosomes arise not by previously described mechanisms, but by a replication template exchange mechanism that does not involve a DNA double-strand break. We thus propose an altern... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088312 Tue, 15 Dec 2009 15:02:55 +0100 3088312 http://www.medworm.com/index.php?rid=3088311&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2861%3Frss%3D1 We report here that a specific pair of nearby inverted repeats in budding yeast fuse to form a dicentric chromosome intermediate, which then rearranges to form a translocation and other GCRs. We next show that fusion of nearby inverted repeats is general; we found that many nearby inverted repeats that are present in the yeast genome also fuse, as does a pair of synthetically constructed inverted repeats. Fusion occurs between inverted repeats that are separated by several kilobases of DNA and share >20 base pairs of homology. Finally, we show that fusion of inverted repeats, surprisingly, does not require genes involved in double-strand break (DSB) repair or genes involved in other repeat recombination events. We therefore propose that fusion may occur by a DSB-independent, DNA replica... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088311 Tue, 15 Dec 2009 15:02:55 +0100 3088311 http://www.medworm.com/index.php?rid=3088310&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2850%3Frss%3D1 This study establishes that intergenic transcription by Pol II is required for siRNA-mediated TGS, and reveals an intricate collaboration and division of labor among the three polymerases in gene silencing. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088310 Tue, 15 Dec 2009 15:02:55 +0100 3088310 http://www.medworm.com/index.php?rid=3088309&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2839%3Frss%3D1 Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Eµ-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088309 Tue, 15 Dec 2009 15:02:55 +0100 3088309 http://www.medworm.com/index.php?rid=3088308&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2824%3Frss%3D1 We reported previously that well-characterized enhancers but not promoters for typical tissue-specific genes, including the classic Alb1 gene, contain unmethylated CpG dinucleotides and evidence of pioneer factor interactions in embryonic stem (ES) cells. These properties, which are distinct from the bivalent histone modification domains that characterize the promoters of genes involved in developmental decisions, raise the possibility that genes expressed only in differentiated cells may need to be marked at the pluripotent stage. Here, we demonstrate that the forkhead family member FoxD3 is essential for the unmethylated mark observed at the Alb1 enhancer in ES cells, with FoxA1 replacing FoxD3 following differentiation into endoderm. Up-regulation of FoxD3 and loss of CpG methylation at... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088308 Tue, 15 Dec 2009 15:02:55 +0100 3088308 http://www.medworm.com/index.php?rid=3088307&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2818%3Frss%3D1 In this study of Drosophila SAGA (dSAGA), we describe three novel components that include an ortholog of Spt20, a potential ortholog of Sgf73/ATXN7, and a novel histone fold protein, SAF6 (SAGA factor-like TAF6). SAF6, which binds directly to TAF9, functions analogously in dSAGA to TAF6/TAF6L in the yeast and human SAGA complexes, respectively. Moreover, TAF6 in flies is restricted to TFIID. Mutations in saf6 disrupt SAGA-regulated gene expression without disrupting acetylated or ubiquitinated histone levels. Thus, SAF6 is essential for SAGA coactivator function independent of the enzymatic activities of the complex. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088307 Tue, 15 Dec 2009 15:02:55 +0100 3088307 http://www.medworm.com/index.php?rid=3088306&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2812%3Frss%3D1 Mammalian life span can be extended by both calorie restriction (CR) and mutations that diminish somatotropic signaling. Sirt1 is a mediator of many effects of CR in mammals, but any role in controlling somatotropic signaling has not been shown. Since the somatotropic axis is controlled by the brain, we created mice lacking Sirt1 specifically in the brain and examined the impacts of this manipulation on somatotropic signaling and the CR response. These mutant mice displayed defects in somatotropic signaling when fed ad libitum, and defects in the endocrine and behavioral responses to CR. We conclude that Sirt1 in the brain is a link between somatotropic signaling and CR in mammals. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088306 Tue, 15 Dec 2009 15:02:55 +0100 3088306 http://www.medworm.com/index.php?rid=3088305&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2806%3Frss%3D1 The miR-17~92 cluster is frequently amplified or overexpressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17~92 is a direct transcriptional target of c-Myc, and experiments in a mouse model of B-cell lymphomas have shown cooperation between these two oncogenes. However, both the molecular mechanism underlying this cooperation and the individual miRNAs that are responsible for it are unknown. By using a conditional knockout allele of miR-17~92, we show here that sustained expression of endogenous miR-17~92 is required to suppress apoptosis in Myc-driven B-cell lymphomas. Furthermore, we show that among the six miRNAs that are encoded by miR-17~92, miR-19a and miR-19b are absolutely required and largely sufficient to recapitulate the onco... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088305 Tue, 15 Dec 2009 15:02:55 +0100 3088305 http://www.medworm.com/index.php?rid=3088304&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2799%3Frss%3D1 Spindle checkpoint silencing is a critical step during mitosis that initiates chromosome segregation, yet surprisingly little is known about its mechanism. Protein phosphatase I (PP1) was shown recently to be a key player in this process, and in this issue of Genes & Deverlopment, Akiyoshi and colleagues (pp. 2887–2899) identify budding yeast Fin1p as a kinetochore-localized regulator of PP1 activity toward checkpoint targets. Here we review recent mechanistic insights and propose a working model for spindle checkpoint silencing. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088304 Tue, 15 Dec 2009 15:02:55 +0100 3088304 http://www.medworm.com/index.php?rid=3088303&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F24%2F2793%3Frss%3D1 Embryonic stem (ES) cells possess a globally open, decondensed chromatin structure that, together with trans-acting factors, supports transcriptional competence of developmentally regulated genes. However, our understanding of the mechanisms that establish transcriptional competence of specific genes is limited. In this issue of Genes & Development, Xu and colleagues (pp. 2824–2838) show that tissue-specific enhancers are actively marked by an unmethylated window in ES cells and induced pluripotent stem (iPS) cells. They propose a model and present supporting evidence to demonstrate the active involvement of pioneer transcription factors in this process. This work marks an important step toward the understanding of the mechanisms that define and maintain pluripotency, and calls f... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3088303 Tue, 15 Dec 2009 15:02:55 +0100 3088303 http://www.medworm.com/index.php?rid=3043403&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2778%3Frss%3D1 The Saccharomyces cerevisiae CLASP (CLIP-associated protein) Stu1 is essential for the establishment and maintenance of the mitotic spindle. Furthermore, Stu1 localizes to kinetochores. Here we show that, in prometaphase, Stu1 assembles in an Ndc80-dependent manner exclusively at kinetochores that are not attached to microtubules. Stu1 relocates to microtubules when a captured kinetochore reaches a spindle pole. This relocation does not depend on kinetochore biorientation, but requires a functional DASH complex. Stu1 at detached kinetochores facilitates kinetochore capturing. Furthermore, since most of the nuclear Stu1 is sequestered by one or a few detached kinetochores, the presence of detached kinetochores prevents Stu1 from localizing the spindle, and therefore from stabilizing the spi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043403 Tue, 01 Dec 2009 15:03:02 +0100 3043403 http://www.medworm.com/index.php?rid=3043402&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2765%3Frss%3D1 This study also shows unambiguously that Paf1C, which is generally thought to have chromatin-related functions, is involve directlyd in elongation control. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043402 Tue, 01 Dec 2009 15:03:02 +0100 3043402 http://www.medworm.com/index.php?rid=3043401&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2753%3Frss%3D1 Most eukaryotic mRNAs are translated using a cap-dependent mechanism of translation. However, ~10% of mammalian mRNAs initiate translation using a cap-independent mechanism that is not well understood. These mRNAs contain an internal ribosome entry site (IRES) located in the 5' untranslated region. The cricket paralysis virus (CrPV) intergenic region IRES (IGR IRES) functions in yeast, mammals, and plants, and does not require any translation initiation factors. We used yeast genetics to understand how ribosomes are recruited directly to the mRNA by an IRES. We found that Rps25p has an essential role in CrPV IGR IRES activity in yeast and mammalian cells but not in cap-dependent translation. Purified 40S ribosomal subunits lacking Rps25 are unable to bind to the IGR IRES in vitro. The hepa... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043401 Tue, 01 Dec 2009 15:03:02 +0100 3043401 http://www.medworm.com/index.php?rid=3043400&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2742%3Frss%3D1 Vasa (Vas) is a DEAD-box RNA-binding protein required in Drosophila at several steps of oogenesis and for primordial germ cell (PGC) specification. Vas associates with eukaryotic initiation factor 5B (eIF5B), and this interaction has been implicated in translational activation of gurken mRNA in the oocyte. Vas is expressed in all ovarian germline cells, and aspects of the vas-null phenotype suggest a function in regulating the balance between germline stem cells (GSCs) and their fate-restricted descendants. We used a biochemical approach to recover Vas-associated mRNAs and obtained mei-P26, whose product represses microRNA activity and promotes GSC differentiation. We found that vas and mei-P26 mutants interact, and that mei-P26 translation is substantially reduced in vas mutant cells. In ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043400 Tue, 01 Dec 2009 15:03:02 +0100 3043400 http://www.medworm.com/index.php?rid=3043399&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2729%3Frss%3D1 We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043399 Tue, 01 Dec 2009 15:03:02 +0100 3043399 http://www.medworm.com/index.php?rid=3043398&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2723%3Frss%3D1 During development, trithorax group (trxG) chromatin remodeling complexes counteract repression by Polycomb group (PcG) complexes to sustain active expression of key regulatory genes. Although PcG complexes are well characterized in plants, little is known about trxG activities. Here we demonstrate that the Arabidopsis SAND (Sp100, AIRE-1, NucP41/75, DEAF-1) domain protein ULTRAPETALA1 (ULT1) functions as a trxG factor that counteracts the PcG-repressive activity of CURLY LEAF. In floral stem cells, ULT1 protein associates directly with the master homeotic locus AGAMOUS, inducing its expression by regulating its histone methylation status. Our analysis introduces a novel mechanism that mediates epigenetic switches controlling post-embryonic stem cell fates in plants. (Source: Genes and Dev... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043398 Tue, 01 Dec 2009 15:03:02 +0100 3043398 http://www.medworm.com/index.php?rid=3043397&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2717%3Frss%3D1 We report that the rdm4 (RNA-directed DNA Methylation4) mutation not only impairs RdDM, but also causes pleiotropic developmental defects in Arabidopsis. Both RNA polymerase II (Pol II)- and Pol V-dependent transcripts are affected in the rdm4 mutant. RDM4 encodes a novel protein that is conserved from yeast to humans and interacts with Pol II and Pol V in plants. Our results suggest that RDM4 functions in epigenetic regulation and plant development by serving as a transcriptional regulator for RNA Pol V and Pol II, respectively. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043397 Tue, 01 Dec 2009 15:03:02 +0100 3043397 http://www.medworm.com/index.php?rid=3043396&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2711%3Frss%3D1 Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis. (Source: Genes ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043396 Tue, 01 Dec 2009 15:03:02 +0100 3043396 http://www.medworm.com/index.php?rid=3043395&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2705%3Frss%3D1 The t complex responder (Tcr) encoded by the mouse t haplotype is able to cause phenotypic differences between t and + sperm derived from t/+ males, leading to non-Mendelian inheritance. This capability of Tcr contradicts the concept of phenotypic equivalence proposed for sperm cells, which develop in a syncytium and actively share gene products. By analyzing a Tcr minigene in hemizygous transgenic mice, we show that Tcr gene products are post-meiotically expressed and are retained in the haploid sperm cells. The wild-type allele of Tcr, sperm motility kinase-1 (Smok1), behaves in the same manner, suggesting that Tcr/Smok reveal a common mechanism prone to evolve non-Mendelian inheritance in mammals. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043395 Tue, 01 Dec 2009 15:03:02 +0100 3043395 http://www.medworm.com/index.php?rid=3043394&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2700%3Frss%3D1 While the global down-regulation of microRNAs (miRNAs) is a common feature of human tumors, its genetic basis is largely undefined. To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 "floxed" or Dicer1fl) on several mouse models of cancer. Here we show Dicer1 functions as a haploinsufficient tumor suppressor gene. Deletion of a single copy of Dicer1 in tumors from Dicer1fl/+ animals led to reduced survival compared with controls. These tumors exhibited impaired miRNA processing but failed to lose the wild-type Dicer1 allele. Moreover, tumors from Dicer1fl/fl animals always maintained one functional Dicer1 allele. Consistent with selection against full loss of Dicer1 expression, enforced Dicer1 deletion caused inhibition of tumorigenesis. Analysis ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043394 Tue, 01 Dec 2009 15:03:02 +0100 3043394 http://www.medworm.com/index.php?rid=3043393&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F23%2F2675%3Frss%3D1 Cell division is commonly thought to involve the equal distribution of cellular components into the two daughter cells. During many cell divisions, however, proteins, membrane compartments, organelles, or even DNA are asymmetrically distributed between the two daughter cells. Here, we review the various types of asymmetries that have been described in yeast and in animal cells. Asymmetric segregation of protein determinants is particularly relevant for stem cell biology. We summarize the relevance of asymmetric cell divisions in various stem cell systems and discuss why defects in asymmetric cell division can lead to the formation of tumors. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=3043393 Tue, 01 Dec 2009 15:03:02 +0100 3043393 http://www.medworm.com/index.php?rid=2995021&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2663%3Frss%3D1 Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNF play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNF shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNF-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNF shedding upon loss of both JunB and c-Jun. Consequently, a prominent TNF-dependent cytokine cascade is initiated in the epidermis, inducing severe skin inflammation and perinatal death of newborns from exha... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995021 Mon, 16 Nov 2009 15:02:32 +0100 2995021 http://www.medworm.com/index.php?rid=2995020&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2650%3Frss%3D1 The locus alx, which encodes a putative transporter, was discovered previously in a screen for genes induced under extreme alkaline conditions. Here we show that the RNA region preceding the alx ORF acts as a pH-responsive element, which, in response to high pH, leads to an increase in alx expression. Under normal growth conditions this RNA region forms a translationally inactive structure, but when exposed to high pH, a translationally active structure is formed to produce Alx. Formation of the active structure occurs while transcription is in progress under alkaline conditions and involves pausing of RNA polymerase at two distinct sites. Alkali increases the longevity of pausing at these sites and thereby interferes with formation of the inactive structure and promotes folding of the act... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995020 Mon, 16 Nov 2009 15:02:32 +0100 2995020 http://www.medworm.com/index.php?rid=2995019&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2639%3Frss%3D1 New types of small RNAs distinct from microRNAs (miRNAs) are progressively being discovered in various organisms. In order to discover such novel small RNAs, a library of 17- to 26-base-long RNAs was created from prostate cancer cell lines and sequenced by ultra-high-throughput sequencing. A significant number of the sequences are derived from precise processing at the 5' or 3' end of mature or precursor tRNAs to form three series of tRFs (tRNA-derived RNA fragments): the tRF-5, tRF-3, and tRF-1 series. These sequences constitute a class of short RNAs that are second most abundant to miRNAs. Northern hybridization, quantitative RT–PCR, and splinted ligation assays independently measured the levels of at least 17 tRFs. To demonstrate the biological importance of tRFs, we further inves... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995019 Mon, 16 Nov 2009 15:02:32 +0100 2995019 http://www.medworm.com/index.php?rid=2995018&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2625%3Frss%3D1 Satb1 and the closely related Satb2 proteins regulate gene expression and higher-order chromatin structure of multigene clusters in vivo. In examining the role of Satb proteins in murine embryonic stem (ES) cells, we find that Satb1–/– cells display an impaired differentiation potential and augmented expression of the pluripotency determinants Nanog, Klf4, and Tbx3. Metastable states of self-renewal and differentiation competence have been attributed to heterogeneity of ES cells in the expression of Nanog. Satb1–/– cultures have a higher proportion of Nanoghigh cells, and an increased potential to reprogram human B lymphocytes in cell fusion experiments. Moreover, Satb1-deficient ES cells show an increased expression of Satb2, and we find that forced Satb2 expressio... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995018 Mon, 16 Nov 2009 15:02:32 +0100 2995018 http://www.medworm.com/index.php?rid=2995017&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2610%3Frss%3D1 Inducible genes in yeast retain a "memory" of recent transcriptional activity during periods of short-term repression, allowing them to be reactivated faster when reinduced. This confers a rapid and versatile gene expression response to the environment. We demonstrate that this memory mechanism is associated with gene loop interactions between the promoter and 3' end of the responsive genes HXK1 and GAL1::FMP27. The maintenance of these memory gene loops (MGLs) during intervening periods of transcriptional repression is required for faster RNA polymerase II (Pol II) recruitment to the genes upon reinduction, thereby facilitating faster mRNA accumulation. Notably, a sua7-1 mutant or the endogenous INO1 gene that lacks this MGL does not display such faster reinduction. Furthermore, these MGL... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995017 Mon, 16 Nov 2009 15:02:32 +0100 2995017 http://www.medworm.com/index.php?rid=2995016&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2604%3Frss%3D1 DNA loops that juxtapose the promoter and terminator regions of RNA polymerase II-transcribed genes have been identified in yeast and mammalian cells. Loop formation is transcription-dependent and requires components of the pre-mRNA 3'-end processing machinery. Here we report that looping at the yeast GAL10 gene persists following a cycle of transcriptional activation and repression. Moreover, GAL10 and a GAL1p-SEN1 reporter undergo rapid reactivation kinetics following a cycle of activation and repression—a phenomenon defined as "transcriptional memory"—and this effect correlates with the persistence of looping. We propose that gene loops facilitate transcriptional memory in yeast. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995016 Mon, 16 Nov 2009 15:02:32 +0100 2995016 http://www.medworm.com/index.php?rid=2995015&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2598%3Frss%3D1 Recent observations highlight that the mammalian genome extensively communicates with itself via long-range chromatin interactions. The causal link between such chromatin cross-talk and epigenetic states is, however, poorly understood. We identify here a network of physically juxtaposed regions from the entire genome with the common denominator of being genomically imprinted. Moreover, CTCF-binding sites within the H19 imprinting control region (ICR) not only determine the physical proximity among imprinted domains, but also transvect allele-specific epigenetic states, identified by replication timing patterns, to interacting, nonallelic imprinted regions during germline development. We conclude that one locus can directly or indirectly pleiotropically influence epigenetic states of multip... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995015 Mon, 16 Nov 2009 15:02:32 +0100 2995015 http://www.medworm.com/index.php?rid=2995014&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2592%3Frss%3D1 It remains unclear whether a microRNA (miRNA) affects a given phenotype via concomitant down-regulation of its entire repertoire of targets or instead by suppression of only a modest subset of effectors. We demonstrate that inhibition of breast cancer metastasis by miR-31—a miRNA predicted to modulate >200 mRNAs—can be entirely explained by miR-31's pleiotropic regulation of three targets. Thus, concurrent re-expression of integrin-5, radixin, and RhoA abrogates miR-31-imposed metastasis suppression. These effectors influence distinct steps of the metastatic process. Our findings have implications concerning the importance of pleiotropy for the biological actions of miRNAs and provide mechanistic insights into metastasis. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995014 Mon, 16 Nov 2009 15:02:32 +0100 2995014 http://www.medworm.com/index.php?rid=2995013&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2578%3Frss%3D1 Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995013 Mon, 16 Nov 2009 15:02:32 +0100 2995013 http://www.medworm.com/index.php?rid=2995012&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F22%2F2563%3Frss%3D1 The epithelium of the mammary gland exists in a highly dynamic state, undergoing dramatic morphogenetic changes during puberty, pregnancy, lactation, and regression. The recent identification of stem and progenitor populations in mouse and human mammary tissue has provided evidence that the mammary epithelium is organized in a hierarchical manner. Characterization of these normal epithelial subtypes is an important step toward understanding which cells are predisposed to oncogenesis. This review summarizes progress in the field toward defining constituent cells and key molecular regulators of the mammary epithelial hierarchy. Potential relationships between normal epithelial populations and breast tumor subtypes are discussed, with implications for understanding the cellular etiology under... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2995012 Mon, 16 Nov 2009 15:02:32 +0100 2995012 http://www.medworm.com/index.php?rid=2949995&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2551%3Frss%3D1 In Xenopus embryos, a dorsal–ventral patterning gradient is generated by diffusing Chordin/bone morphogenetic protein (BMP) complexes cleaved by BMP1/Tolloid metalloproteinases in the ventral side. We developed a new BMP1/Tolloid assay using a fluorogenic Chordin peptide substrate and identified an unexpected negative feedback loop for BMP4, in which BMP4 inhibits Tolloid enzyme activity noncompetitively. BMP4 binds directly to the CUB (Complement 1r/s, Uegf [a sea urchin embryonic protein] and BMP1) domains of BMP1 and Drosophila Tolloid with high affinity. Binding to CUB domains inhibits BMP4 signaling. These findings provide a molecular explanation for a long-standing genetical puzzle in which antimorphic Drosophila tolloid mutant alleles displayed anti-BMP effects. The extensive ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949995 Mon, 02 Nov 2009 15:02:22 +0100 2949995 http://www.medworm.com/index.php?rid=2949994&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2537%3Frss%3D1 Mammalian mRNAs lose and acquire proteins throughout their life span while undergoing processing, transport, translation, and decay. How translation affects messenger RNA (mRNA)–protein interactions is largely unknown. The pioneer round of translation uses newly synthesized mRNA that is bound by cap-binding protein 80 (CBP80)–CBP20 (also known as the cap-binding complex [CBC]) at the cap, poly(A)-binding protein N1 (PABPN1) and PABPC1 at the poly(A) tail, and, provided biogenesis involves pre-mRNA splicing, exon junction complexes (EJCs) at exon–exon junctions. Subsequent rounds of translation engage mRNA that is bound by eukaryotic translation initiation factor 4E (eIF4E) at the cap and PABPC1 at the poly(A) tail, but that lacks detectable EJCs and PABPN1. Using the leve... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949994 Mon, 02 Nov 2009 15:02:22 +0100 2949994 http://www.medworm.com/index.php?rid=2949993&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2521%3Frss%3D1 Despite the identification of some key genes that regulate sex determination, most cases of disorders of sexual development remain unexplained. Evidence suggests that the sexual fate decision in the developing gonad depends on a complex network of interacting factors that converge on a critical threshold. To elucidate the transcriptional network underlying sex determination, we took the first expression quantitative trait loci (eQTL) approach in a developing organ. We identified reproducible differences in the transcriptome of the embryonic day 11.5 (E11.5) XY gonad between C57BL/6J (B6) and 129S1/SvImJ (129S1), indicating that the reported sensitivity of B6 to sex reversal is consistent with a higher expression of a female-like transcriptome in B6. Gene expression is highly variable in F2... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949993 Mon, 02 Nov 2009 15:02:22 +0100 2949993 http://www.medworm.com/index.php?rid=2949992&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2507%3Frss%3D1 The histone H3 Lys 9 (H3K9) methyltransferase Eset is an epigenetic regulator critical for the development of the inner cell mass (ICM). Although ICM-derived embryonic stem (ES) cells are normally unable to contribute to the trophectoderm (TE) in blastocysts, we find that depletion of Eset by shRNAs leads to differentiation with the formation of trophoblast-like cells and induction of trophoblast-associated gene expression. Using chromatin immmunoprecipitation (ChIP) and sequencing (ChIP-seq) analyses, we identified Eset target genes with Eset-dependent H3K9 trimethylation. We confirmed that genes that are preferentially expressed in the TE (Tcfap2a and Cdx2) are bound and repressed by Eset. Single-cell PCR analysis shows that the expression of Cdx2 and Tcfap2a is also induced in Eset-depl... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949992 Mon, 02 Nov 2009 15:02:22 +0100 2949992 http://www.medworm.com/index.php?rid=2949991&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2496%3Frss%3D1 Plants have developed their own defense strategies because they have no immune cells. A common plant defense strategy involves programmed cell death (PCD) at the infection site, but how the PCD-associated cell-autonomous immunity is executed in plants is not fully understood. Here we provide a novel mechanism underlying cell-autonomous immunity, which involves the fusion of membranes of a large central vacuole with the plasma membrane, resulting in the discharge of vacuolar antibacterial proteins to the outside of the cells, where bacteria proliferate. The extracellular fluid that was discharged from the vacuoles of infected leaves had both antibacterial activity and cell death-inducing activity. We found that a defect in proteasome function abolished the membrane fusion associated with bo... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949991 Mon, 02 Nov 2009 15:02:22 +0100 2949991 http://www.medworm.com/index.php?rid=2949990&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2490%3Frss%3D1 The dosage compensation complex (DCC) in Drosophila globally increases transcription from the X chromosome in males to compensate for its monosomy. We discovered a male-specific conformation of the X chromosome that depends on the associations of high-affinity binding sites (HAS) of the DCC. The core DCC subunits MSL1–MSL2 are responsible for this male-specific organization. Contrary to emerging concepts, we found that neither DCC assembly nor the conformation of the male X chromosome are influenced by nuclear pore components. We propose that nuclear organization of HAS is central to the faithful distribution of the DCC along the X chromosome. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949990 Mon, 02 Nov 2009 15:02:22 +0100 2949990 http://www.medworm.com/index.php?rid=2949989&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2484%3Frss%3D1 Transcription factors that play key roles in regulating embryonic stem (ES) cell state have been identified, but the chromatin regulators that help maintain ES cells are less well understood. A high-throughput shRNA screen was used to identify novel chromatin regulators that influence ES cell state. Loss of histone H3 Lys 9 (H3K9) methyltransferases, particularly SetDB1, had the most profound effects on ES cells. Chromatin immunoprecipitation (ChIP) coupled with massively parallel DNA sequencing (ChIP-Seq) and functional analysis revealed that SetDB1 and histone H3K9-methylated nucleosomes occupy and repress genes encoding developmental regulators. These SetDB1-occupied genes are a subset of the "bivalent" genes, which contain nucleosomes with H3K4me3 (H3K4 trimethylation) and H3K27me3 mod... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949989 Mon, 02 Nov 2009 15:02:22 +0100 2949989 http://www.medworm.com/index.php?rid=2949988&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2478%3Frss%3D1 Programmed genome rearrangements drive functional gene assembly in ciliates during the development of the somatic macronucleus. The elimination of germline sequences is directed by noncoding RNAs and is initiated by DNA double-strand breaks, but the enzymes responsible for DNA cleavage have not been identified. We show here that PiggyMac (Pgm), a domesticated piggyBac transposase, is required for these rearrangements in Paramecium tetraurelia. A GFP-Pgm fusion localizes in developing macronuclei, where rearrangements take place, and RNAi-mediated silencing of PGM abolishes DNA cleavage. This is the first in vivo evidence suggesting an essential endonucleolytic function of a domesticated piggyBac transposase. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949988 Mon, 02 Nov 2009 15:02:22 +0100 2949988 http://www.medworm.com/index.php?rid=2949987&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2461%3Frss%3D1 A great many cell types are necessary for the myriad capabilities of complex, multicellular organisms. One interesting aspect of this diversity of cell type is that many cells in diploid organisms are polyploid. This is called endopolyploidy and arises from cell cycles that are often characterized as "variant," but in fact are widespread throughout nature. Endopolyploidy is essential for normal development and physiology in many different organisms. Here we review how both plants and animals use variations of the cell cycle, termed collectively as endoreplication, resulting in polyploid cells that support specific aspects of development. In addition, we discuss briefly how endoreplication occurs in response to certain physiological stresses, and how it may contribute to the development of ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949987 Mon, 02 Nov 2009 15:02:22 +0100 2949987 http://www.medworm.com/index.php?rid=2949986&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2455%3Frss%3D1 The ciliate Paramecium tetraurelia must eliminate ~60,000 short sequences from its genome to generate uninterrupted coding sequences in its somatic macronucleus. In this issue of Genes & Development, Baudry and colleagues (pp. 2478–2483) identify the protein that excises these noncoding sequences: a domesticated piggyBac transposase that has been adapted to remove what are likely the remnants of transposon insertions. This new study reveals how addition of a transposase to small RNA-directed silencing machinery can guide major genome reorganization. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949986 Mon, 02 Nov 2009 15:02:22 +0100 2949986 http://www.medworm.com/index.php?rid=2949985&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F21%2F2449%3Frss%3D1 Eukaryotes have evolved various means for controlled and organized cellular destruction, known as programmed cell death (PCD). In plants, PCD is a crucial regulatory mechanism in multiple physiological processes, including terminal differentiation, senescence, and disease resistance. In this issue of Genes & Development, Hatsugai and colleagues (pp. 2496–2506) demonstrate a novel plant defense strategy to trigger bacteria-induced PCD, involving proteasome-dependent tonoplast and plasma membrane fusion followed by discharge of vacuolar antimicrobial and death-inducing contents into the apoplast. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2949985 Mon, 02 Nov 2009 15:02:22 +0100 2949985 http://www.medworm.com/index.php?rid=2893459&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2437%3Frss%3D1 Human cells contain several hundred ribosomal genes (rDNA) that are clustered into nucleolar organizer regions (NORs) on the short arms of five different acrocentric chromosomes. Only ~50% of the gene copies are actually expressed in somatic cells. Here, we used a new cytological technique to demonstrate that rDNA is regulated allelically in a regional manner, with one parental copy of each NOR being repressed in any individual cell. This process is similar to that of X-chromosome inactivation in females. Early in development, one copy of each NOR becomes late-replicating, thus probably marking it for inactivation and subsequent targeted de novo methylation at rDNA promoter regions. Once established, this multichromosomal allelic pattern is then maintained clonally in somatic cells. This p... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893459 Thu, 15 Oct 2009 14:02:53 +0100 2893459 http://www.medworm.com/index.php?rid=2893458&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2426%3Frss%3D1 In bacteria, multiple s direct RNA polymerase to distinct sets of promoters. Housekeeping s direct transcription from thousands of promoters, whereas most alternative s are more selective, recognizing more highly conserved promoter motifs. For 32 and 28, two Escherichia coli Group 3 s, altering a few residues in Region 2.3, the portion of implicated in promoter melting, to those universally conserved in housekeeping s relaxed their stringent promoter requirements and significantly enhanced melting of suboptimal promoters. All Group 3 s and the more divergent Group 4 s have nonconserved amino acids at these positions and rarely transcribe >100 promoters. We suggest that the balance of "melting" and "recognition" functions of s is critical to setting the stringency of promoter recognition... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893458 Thu, 15 Oct 2009 14:02:53 +0100 2893458 http://www.medworm.com/index.php?rid=2893457&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2415%3Frss%3D1 The integrity of genomic DNA is continuously challenged by the presence of DNA base lesions or DNA strand breaks. Here we report the identification of a new DNA damage response protein, SMARCAL1 (SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily a-like 1), which is a member of the SNF2 family and is mutated in Schimke immunoosseous dysplasia (SIOD). We demonstrate that SMARCAL1 directly interacts with Replication protein A (RPA) and is recruited to sites of DNA damage in an RPA-dependent manner. SMARCAL1-depleted cells display sensitivity to DNA-damaging agents that induce replication fork collapse, and exhibit slower fork recovery and delayed entry into mitosis following S-phase arrest. Furthermore, SIOD patient fibroblasts reconstituted with SMARCAL1 e... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893457 Thu, 15 Oct 2009 14:02:53 +0100 2893457 http://www.medworm.com/index.php?rid=2893456&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2405%3Frss%3D1 Mutations in SMARCAL1 (HARP) cause Schimke immunoosseous dysplasia (SIOD). The mechanistic basis for this disease is unknown. Using functional genomic screens, we identified SMARCAL1 as a genome maintenance protein. Silencing and overexpression of SMARCAL1 leads to activation of the DNA damage response during S phase in the absence of any genotoxic agent. SMARCAL1 contains a Replication protein A (RPA)-binding motif similar to that found in the replication stress response protein TIPIN (Timeless-Interacting Protein), which is both necessary and sufficient to target SMARCAL1 to stalled replication forks. RPA binding is critical for the cellular function of SMARCAL1; however, it is not necessary for the annealing helicase activity of SMARCAL1 in vitro. An SIOD-associated SMARCAL1 mutant fail... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893456 Thu, 15 Oct 2009 14:02:53 +0100 2893456 http://www.medworm.com/index.php?rid=2893455&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2400%3Frss%3D1 HepA-related protein (HARP) (also known as SMARCAL1) is an ATP-driven annealing helicase that catalyzes the formation of dsDNA from complementary Replication protein A (RPA)-bound ssDNA. Here we find that HARP contains a conserved N-terminal motif that is necessary and sufficient for binding to RPA. This RPA-binding motif is not required for annealing helicase activity, but is essential for the recruitment of HARP to sites of laser-induced DNA damage. These findings suggest that the interaction of HARP with RPA increases the concentration of annealing helicase activity in the vicinity of ssDNA regions to facilitate processes such as DNA repair. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893455 Thu, 15 Oct 2009 14:02:53 +0100 2893455 http://www.medworm.com/index.php?rid=2893454&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2394%3Frss%3D1 Mutations in HepA-related protein (HARP) are the only identified causes of Schimke immunoosseous dysplasia (SIOD). HARP has a unique annealing helicase activity in vitro, but the in vivo functional significance remains unknown. Here, we demonstrated that HARP is recruited to stalled replication forks via its direct interaction with Replication protein A (RPA). Cells with HARP depletion displayed increased spontaneous DNA damage and G2/M arrest, suggesting that HARP normally acts to stabilize stalled replication forks. Our data place the annealing helicase activity of HARP at replication forks and propose that SIOD syndrome may be caused by the destabilization of replication forks during cell proliferation. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893454 Thu, 15 Oct 2009 14:02:52 +0100 2893454 http://www.medworm.com/index.php?rid=2893453&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2388%3Frss%3D1 The Rb–E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb–E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of miR-449a/b. Our study reveals a tumor suppressor function of miR-449a/b through regulating Rb/E2F1 activity, and suggests that escape from this regulation through an aber... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893453 Thu, 15 Oct 2009 14:02:52 +0100 2893453 http://www.medworm.com/index.php?rid=2893452&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2382%3Frss%3D1 Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B, which mediate cytokine signaling. To reveal the underlying causes for this developmental block, we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and its ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Thus, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893452 Thu, 15 Oct 2009 14:02:52 +0100 2893452 http://www.medworm.com/index.php?rid=2893451&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2376%3Frss%3D1 Common lymphoid progenitors (CLPs) clonally produce both B- and T-cell lineages, but have little myeloid potential in vivo. However, some studies claim that the upstream lymphoid-primed multipotent progenitor (LMPP) is the thymic seeding population, and suggest that CLPs are primarily B-cell-restricted. To identify surface proteins that distinguish functional CLPs from B-cell progenitors, we used a new computational method of Mining Developmentally Regulated Genes (MiDReG). We identified Ly6d, which divides CLPs into two distinct populations: one that retains full in vivo lymphoid potential and produces more thymocytes at early timepoints than LMPP, and another that behaves essentially as a B-cell progenitor. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893451 Thu, 15 Oct 2009 14:02:52 +0100 2893451 http://www.medworm.com/index.php?rid=2893450&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2371%3Frss%3D1 A key step in bacterial transcription initiation is melting of the double-stranded promoter DNA by the RNA polymerase holoenzyme. Primary factors mediate the melting of thousands of promoters through a conserved set of aromatic amino acids. Alternative s, which direct transcription of restricted regulons, lack the full set of melting residues. In this issue of Genes & Development, Koo and colleagues (pp. 2426–2436) show that introducing the primary melting residues into alternative s relaxes their promoter specificity, pointing to a trade-off of reduced promoter melting capacity for increased promoter stringency. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893450 Thu, 15 Oct 2009 14:02:52 +0100 2893450 http://www.medworm.com/index.php?rid=2893449&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2366%3Frss%3D1 The paths that hematopoietic stem cells take to develop from multipotent, self-renewing cells into committed lymphocytes has been a topic of debate for some time. During early hematopoiesis, multiple branchpoints have been described in which progeny cells segregate into cell lineages with distinct developmental potentials. In this issue of Genes & Development, Inlay and colleagues (pp. 2376–2381) identify novel intermediate stages through which hematopoietic progenitor cells travel. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893449 Thu, 15 Oct 2009 14:02:52 +0100 2893449 http://www.medworm.com/index.php?rid=2893448&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F20%2F2359%3Frss%3D1 In this issue of Genes & Development, four papers report that the annealing helicase HepA-related protein (HARP, also known as SMARCAL1 [SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1]) binds directly to the ssDNA-binding protein Replication protein A (RPA) and is recruited to sites of replicative stress. Knockdown of HARP results in hypersensitivity to multiple DNA-damaging agents and defects in fork stability or restart. These exciting insights reveal a key new player in the S-phase DNA damage response. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2893448 Thu, 15 Oct 2009 14:02:52 +0100 2893448 http://www.medworm.com/index.php?rid=2854432&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2358%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854432 Thu, 01 Oct 2009 20:58:29 +0100 2854432 http://www.medworm.com/index.php?rid=2854431&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2345%3Frss%3D1 Cohesins mediate sister chromatid cohesion and DNA repair and also function in gene regulation. Chromosomal cohesins are distributed nonrandomly, and their deposition requires the heterodimeric Scc2/Scc4 loader. Whether Scc2/Scc4 establishes nonrandom cohesin distributions on chromosomes is poorly characterized, however. To better understand the spatial regulation of cohesin association, we mapped budding yeast Scc2 and Scc4 chromosomal distributions. We find that Scc2/Scc4 resides at previously mapped cohesin-associated regions (CARs) in pericentromeric and arm regions, and that Scc2/Scc4–cohesin colocalization persists after the initial deposition of cohesins in G1/S phase. Pericentromeric Scc2/Scc4 enrichment is kinetochore-dependent, and both Scc2/Scc4 and cohesin associations ar... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854431 Thu, 01 Oct 2009 20:58:29 +0100 2854431 http://www.medworm.com/index.php?rid=2854430&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2333%3Frss%3D1 Gut homeostasis is controlled by both immune and developmental mechanisms, and its disruption can lead to inflammatory disorders or cancerous lesions of the intestine. While the impact of bacteria on the mucosal immune system is beginning to be precisely understood, little is known about the effects of bacteria on gut epithelium renewal. Here, we addressed how both infectious and indigenous bacteria modulate stem cell activity in Drosophila. We show that the increased epithelium renewal observed upon some bacterial infections is a consequence of the oxidative burst, a major defense of the Drosophila gut. Additionally, we provide evidence that the JAK–STAT (Janus kinase–signal transducers and activators of transcription) and JNK (c-Jun NH2 terminal kinase) pathways are both requ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854430 Thu, 01 Oct 2009 20:58:29 +0100 2854430 http://www.medworm.com/index.php?rid=2854429&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2320%3Frss%3D1 We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR+] (for "resistant to glucose-associated repression," with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR+] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. The Pma1 proteins from closely related Saccharomyces species are also associated with the appearance of [GAR+]. This allowed us to confirm the relationship between Pma1, ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854429 Thu, 01 Oct 2009 20:58:29 +0100 2854429 http://www.medworm.com/index.php?rid=2854428&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2307%3Frss%3D1 The accurate control of cell proliferation and survival is critical for animal development. The Hippo tumor suppressor pathway regulates both of these parameters by controlling the nuclear availability of the transcriptional coactivator Yorkie (Yki), which regulates downstream target genes together with Scalloped (Sd), a DNA-binding protein. Here we provide evidence that Yki can also regulate target genes in conjunction with Homothorax (Hth) and Teashirt (Tsh), two DNA-binding transcription factors expressed in the uncommitted progenitor cells of the Drosophila eye imaginal disc. Clonal analyses demonstrate that Hth and Tsh promote cell proliferation and protect eye progenitor cells from apoptosis. Genetic epistasis experiments suggest that Hth and Tsh execute these functions with Yki, in ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854428 Thu, 01 Oct 2009 20:58:29 +0100 2854428 http://www.medworm.com/index.php?rid=2854427&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2294%3Frss%3D1 Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in lysosome-mediated protein degradation. To validate these observations in vivo, we generated mutant SOD1 transge... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854427 Thu, 01 Oct 2009 20:58:29 +0100 2854427 http://www.medworm.com/index.php?rid=2854426&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2284%3Frss%3D1 Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated in a variety of neurological diseases, can counteract the effects of chronic depolarization on splicing. We find that exon 19 of Fox-1 is itself repressed by depol... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854426 Thu, 01 Oct 2009 20:58:28 +0100 2854426 http://www.medworm.com/index.php?rid=2854425&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2278%3Frss%3D1 Vascular smooth muscle cells (VSMCs) form contractile layers around larger blood vessels in a process that is essential for the formation of a fully functional vasculature. Here, we show that integrin-linked kinase (ILK) is required for the formation of a unitary layer of aligned VSMCs around arterioles and the regulation of blood vessel constriction in mice. In the absence of ILK, activated Rho/ROCK signaling induces the elevated phosphorylation of myosin light chain leading to abnormally enhanced VSMC contraction in vitro and in vivo. Our findings identify ILK as a key component regulating vascular wall formation by negatively modulating VSMC contractility. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854425 Thu, 01 Oct 2009 20:58:28 +0100 2854425 http://www.medworm.com/index.php?rid=2854424&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2272%3Frss%3D1 The aorta traverses the body, yet little is known about how it is patterned in different anatomical locations. Here, we show that the aorta develops from genetically distinct endothelial cells originating from diverse locations within the embryo. Furthermore, chemokine (C-X-C motif) receptor 4a (cxcr4a) is restricted to endothelial cells derived from anterior mesoderm, and is required specifically for formation of the lateral aortae. Cxcl12b, a cxcr4a ligand, is expressed in endoderm underlying the lateral aortae, and loss of cxcl12b phenocopies cxcr4a deficiency. These studies reveal unexpected endothelial diversity within the aorta that is necessary to facilitate its regional patterning by local cues. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854424 Thu, 01 Oct 2009 20:58:28 +0100 2854424 http://www.medworm.com/index.php?rid=2854423&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2266%3Frss%3D1 Dosage compensation in Drosophila melanogaster males is achieved via targeting of male-specific lethal (MSL) complex to X-linked genes. This is proposed to involve sequence-specific recognition of the X at ~150–300 chromatin entry sites, and subsequent spreading to active genes. Here we ask whether the spreading step requires transcription and is sequence-independent. We find that MSL complex binds, acetylates, and up-regulates autosomal genes inserted on X, but only if transcriptionally active. We conclude that a long-sought specific DNA sequence within X-linked genes is not obligatory for MSL binding. Instead, linkage and transcription play the pivotal roles in MSL targeting irrespective of gene origin and DNA sequence. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854423 Thu, 01 Oct 2009 20:58:28 +0100 2854423 http://www.medworm.com/index.php?rid=2854422&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2260%3Frss%3D1 Although it is widely accepted that dynamic cross-talk between gut epithelia and microorganisms must occur to achieve gut homeostasis, the critical mechanisms by which gut–microbe interactions are regulated remain uncertain. In this issue of Genes & Development, Buchon and colleagues (pp. 2333–2344) revealed that the reaction of the gut to microorganisms is not restricted to activating immune systems, but extends to integrated responses essential for gut tissue homeostasis, including self-renewal and the differentiation of stem cells. Further investigation of the connection between immune response and stem cell regulation at the molecular level in the microbe-laden mucosal epithelia will accelerate our understanding of the regulatory mechanisms of gut homeostasis and of the... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854422 Thu, 01 Oct 2009 20:58:28 +0100 2854422 http://www.medworm.com/index.php?rid=2854421&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F19%2F2253%3Frss%3D1 Cellular defense mechanisms, including the unfolded protein response (UPR) and autophagy, attempt to resolve toxic protein aggregates, which are common denominators of neurodegenerative diseases. In this issue of Genes & Development, Hetz and colleagues (pp. 2294–2306) surprisingly show that inhibition of the UPR by knockout of XBP-1 causes a massive increase in autophagy, enhances clearance of superoxide dismutase 1 (SOD1) aggregates, and delays the development of amyotrophic lateral sclerosis. These findings suggest the existence of a homeostatic—if not hormetic—balance between distinct cellular defense mechanisms. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2854421 Thu, 01 Oct 2009 20:58:28 +0100 2854421 http://www.medworm.com/index.php?rid=2799367&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2237%3Frss%3D1 Several protein kinases collaborate to orchestrate and integrate cellular and chromosomal events at the G2/M transition in both mitotic and meiotic cells. During the G2/M transition in meiosis, this includes the completion of crossover recombination, spindle formation, and synaptonemal complex (SC) breakdown. We identified Ipl1/Aurora B kinase as the main regulator of SC disassembly. Mutants lacking Ipl1 or its kinase activity assemble SCs with normal timing, but fail to dissociate the central element component Zip1, as well as its binding partner, Smt3/SUMO, from chromosomes in a timely fashion. Moreover, lack of Ipl1 activity causes delayed SC disassembly in a cdc5 as well as a CDC5-inducible ndt80 mutant. Crossover levels in the ipl1 mutant are similar to those observed in wild type, in... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799367 Tue, 15 Sep 2009 23:00:00 +0100 2799367 http://www.medworm.com/index.php?rid=2799366&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2224%3Frss%3D1 The cohesin complex establishes sister chromatid cohesion during S phase. In metazoan cells, most if not all cohesin dissociates from chromatin during mitotic prophase, leading to the formation of metaphase chromosomes with two cytologically discernible chromatids. This process, known as sister chromatid resolution, is believed to be a prerequisite for synchronous separation of sister chromatids in subsequent anaphase. To dissect this process at a mechanistic level, we set up an in vitro system. Sister chromatid resolution is severely impaired upon depletion of Wapl from Xenopus egg extracts. Exogenously added human Wapl can rescue these defects and, remarkably, it can do so in a very short time window of early mitosis. A similar set of observations is made for Pds5, a factor implicated pr... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799366 Tue, 15 Sep 2009 23:00:00 +0100 2799366 http://www.medworm.com/index.php?rid=2799365&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2210%3Frss%3D1 Development of the germline requires consecutive differentiation events. Regulation of these has been associated with germ cell-specific and pluripotency-associated transcription factors, but the role of general transcription factors (GTFs) remains elusive. TATA-binding protein (TBP) is a GTF involved in transcription by all RNA polymerases. During ovarian folliculogenesis in mice the vertebrate-specific member of the TBP family, TBP2/TRF3, is expressed exclusively in oocytes. To determine TBP2 function in vivo, we generated TBP2-deficient mice. We found that Tbp2–/– mice are viable with no apparent phenotype. However, females lacking TBP2 are sterile due to defective folliculogenesis, altered chromatin organization, and transcriptional misregulation of key oocyte-specific gene... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799365 Tue, 15 Sep 2009 23:00:00 +0100 2799365 http://www.medworm.com/index.php?rid=2799364&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2201%3Frss%3D1 Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erb tightly controls the level of its own ligand. Heme binding to Rev-erb recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1, a potent inducer of heme synthesis. Depletion of Rev-erb derepresses PGC-1, resulting in increased heme levels. Conversely, increased Rev-erb reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erb dramatically inhibits cell... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799364 Tue, 15 Sep 2009 23:00:00 +0100 2799364 http://www.medworm.com/index.php?rid=2799363&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2192%3Frss%3D1 We present a mathematical model that describes the cytoplasmic accumulation of wild-type and mutant FRQ on a circadian time scale on the basis of frequency-modulated rapid nucleocytoplasmic shuttling cycles. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799363 Tue, 15 Sep 2009 23:00:00 +0100 2799363 http://www.medworm.com/index.php?rid=2799362&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2179%3Frss%3D1 Little is known about the contribution of translational control to circadian rhythms. To address this issue and in particular translational control by microRNAs (miRNAs), we knocked down the miRNA biogenesis pathway in Drosophila circadian tissues. In combination with an increase in circadian-mediated transcription, this severely affected Drosophila behavioral rhythms, indicating that miRNAs function in circadian timekeeping. To identify miRNA–mRNA pairs important for this regulation, immunoprecipitation of AGO1 followed by microarray analysis identified mRNAs under miRNA-mediated control. They included three core clock mRNAs—clock (clk), vrille (vri), and clockworkorange (cwo). To identify miRNAs involved in circadian timekeeping, we exploited circadian cell-specific inhibitio... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799362 Tue, 15 Sep 2009 23:00:00 +0100 2799362 http://www.medworm.com/index.php?rid=2799361&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2166%3Frss%3D1 Vascular injury triggers dedifferentiation and cytoskeletal remodeling of smooth muscle cells (SMCs), culminating in vessel occlusion. Serum response factor (SRF) and its coactivator, myocardin, play a central role in the control of smooth muscle phenotypes by regulating the expression of cytoskeletal genes. We show that SRF and myocardin regulate a cardiovascular-specific microRNA (miRNA) cluster encoding miR-143 and miR-145. To assess the functions of these miRNAs in vivo, we systematically deleted them singly and in combination in mice. Mice lacking both miR-143 and miR-145 are viable and do not display overt abnormalities in smooth muscle differentiation, although they show a significant reduction in blood pressure due to reduced vascular tone. Remarkably, however, neointima formation ... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799361 Tue, 15 Sep 2009 23:00:00 +0100 2799361 http://www.medworm.com/index.php?rid=2799360&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2152%3Frss%3D1 While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in prim... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799360 Tue, 15 Sep 2009 23:00:00 +0100 2799360 http://www.medworm.com/index.php?rid=2799359&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2140%3Frss%3D1 Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-β or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreas... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799359 Tue, 15 Sep 2009 23:00:00 +0100 2799359 http://www.medworm.com/index.php?rid=2799358&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2134%3Frss%3D1 Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier. Expression of the four reprogramming factors triggers senescence by up-regulating p53, p16INK4a, and p21CIP1. Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799358 Tue, 15 Sep 2009 23:00:00 +0100 2799358 http://www.medworm.com/index.php?rid=2799357&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2124%3Frss%3D1 Genomic imprinting refers to an epigenetic mark that distinguishes parental alleles and results in a monoallelic, parental-specific expression pattern in mammals. Few phenomena in nature depend more on epigenetic mechanisms while at the same time evading them. The alleles of imprinted genes are marked epigenetically at discrete elements termed imprinting control regions (ICRs) with their parental origin in gametes through the use of DNA methylation, at the very least. Imprinted gene expression is subsequently maintained using noncoding RNAs, histone modifications, insulators, and higher-order chromatin structure. Avoidance is manifest when imprinted genes evade the genome-wide reprogramming that occurs after fertilization and remain marked with their parental origin. This review summarizes... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799357 Tue, 15 Sep 2009 23:00:00 +0100 2799357 http://www.medworm.com/index.php?rid=2799356&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F18%2F2117%3Frss%3D1 Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882–1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-B ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases. (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2799356 Tue, 15 Sep 2009 23:00:00 +0100 2799356 http://www.medworm.com/index.php?rid=2756059&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2116%3Frss%3D1 (Source: Genes and Development) Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756059 Mon, 31 Aug 2009 23:00:00 +0100 2756059 http://www.medworm.com/index.php?rid=2756058&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2102%3Frss%3D1 Yeast senses the availability of external energy sources via multiple interconnected signaling networks. One of the central components is SNF1, the homolog of mammalian AMP-activated protein kinase, which in yeast is essential for the expression of glucose-repressed genes. When glucose is available hyperphosphorylated SNF1 is rendered inactive by the type 1 protein phosphatase Glc7. Dephosphorylation requires Reg1, which physically targets Glc7 to SNF1. Here we show that the chaperone Ssb is required to keep SNF1 in the nonphosphorylated state in the presence of glucose. Using a proteome approach we found that the ssb1ssb2 strain displays alterations in protein expression and suffers from phenotypic characteristics reminiscent of glucose repression mutants. Microarray analysis revealed a c... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756058 Mon, 31 Aug 2009 23:00:00 +0100 2756058 http://www.medworm.com/index.php?rid=2756057&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2088%3Frss%3D1 Canonical Notch signaling is thought to control the endocrine/exocrine decision in early pancreatic progenitors. Later, RBP-J interacts with Ptf1a and E12 to promote acinar differentiation. To examine the involvement of Notch signaling in selecting specific endocrine lineages, we deregulated this pathway by targeted deletion of presenilin1 and presenilin2, the catalytic core of -secretase, in Ngn3- or Pax6-expressing endocrine progenitors. Surprisingly, whereas Pax6+ progenitors were irreversibly committed to the endocrine fate, we discovered that Ngn3+ progenitors were bipotential in vivo and in vitro. When presenilin amounts are limiting, Ngn3+ progenitors default to an acinar fate; subsequently, they expand rapidly to form the bulk of the exocrine pancreas. -Secretase inhibitors confirm... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756057 Mon, 31 Aug 2009 23:00:00 +0100 2756057 http://www.medworm.com/index.php?rid=2756056&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2076%3Frss%3D1 A major question in hematopoiesis is how the system maintains long-term homeostasis whereby the generation of large numbers of differentiated cells is balanced with the requirement for maintenance of progenitor pools, while remaining sufficiently flexible to respond to periods of perturbed cellular output during infection or stress. We focused on the development of the myeloid lineage and present evidence that promyelocytic leukemia zinc finger (PLZF) provides a novel function that is critical for both normal and stress-induced myelopoiesis. During homeostasis, PLZF restricts proliferation and differentiation of human cord blood-derived myeloid progenitors to maintain a balance between the progenitor and mature cell compartments. Analysis of PLZF promoter-binding sites revealed that it rep... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756056 Mon, 31 Aug 2009 23:00:00 +0100 2756056 http://www.medworm.com/index.php?rid=2756055&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2060%3Frss%3D1 The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric -H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric sign... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756055 Mon, 31 Aug 2009 23:00:00 +0100 2756055 http://www.medworm.com/index.php?rid=2756054&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2046%3Frss%3D1 Centrioles are subcellular organelles composed of a ninefold symmetric microtubule array that perform two important functions: (1) They build centrosomes that organize the microtubule cytoskeleton, and (2) they template cilia, microtubule-based projections with sensory and motile functions. We identified HYLS-1, a widely conserved protein, based on its direct interaction with the core centriolar protein SAS-4. HYLS-1 localization to centrioles requires SAS-4 and, like SAS-4, HYLS-1 is stably incorporated into the outer centriole wall. Unlike SAS-4, HYLS-1 is dispensable for centriole assembly and centrosome function in cell division. Instead, HYLS-1 plays an essential role in cilia formation that is conserved between Caenorhabditis elegans and vertebrates. A single amino acid change in hum... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756054 Mon, 31 Aug 2009 23:00:00 +0100 2756054 http://www.medworm.com/index.php?rid=2756053&cid=s_33049_50_f&fid=33049&url=http%3A%2F%2Fgenesdev.cshlp.org%2Fcgi%2Fcontent%2Fshort%2F23%2F17%2F2033%3Frss%3D1 During or right after mRNA export via the nuclear pore complex (NPC) in mammalian cells, mRNAs undergo translation mediated by nuclear cap-binding proteins 80 and 20 (CBP80/20). After CBP80/20-dependent translation, CBP80/20 is replaced by cytoplasmic cap-binding protein eIF4E, which directs steady-state translation. Nonsense-mediated mRNA decay (NMD), one of the best-characterized mRNA surveillance mechanisms, has been shown to occur on CBP80/20-bound mRNAs. However, despite the tight link between CBP80/20-dependent translation and NMD, the underlying molecular mechanism and cellular factors that mediate CBP80/20-dependent translation remain obscure. Here, we identify a new MIF4G domain-containing protein, CTIF (CBP80/20-dependent translation initiation factor). CTIF interacts directly wi... Genes and Development journals http://www.medworm.com/rss/comments.php?id=2756053 Mon, 31 Aug 2009 23:00:00 +0100 2756053