Deletion of phospholipase A2 group IV c induces apoptosis in rat mammary tumor cells by the nuclear factor-{kappa}B/lipocalin 2 pathway
Although some phospholipase A2 forms, the initiator of the arachidonic acid cascade, contribute to carcinogenesis in many organs, the contribution of phospholipase A2 group IVc (Pla2g4c) remains to be clarified and the function of the enzyme in cancer development are unknown. The Hirosaki hairless rat (HHR), a mutant rat strain with autosomal recessive inheritance, spontaneously derived from the Sprague-Dawley rat (SDR). The HHR showed the low incidence, volume of mammary tumors induced by 7,12-dimethylbenz[a]anthracene were much smaller, and markedly increased TUNEL-positive apoptotic cells were detected. Array comparativ...
Source: BJ Disease - May 27, 2015 Category: Biochemistry Authors: N Nanashima, T Yamada, T Shimizu, S Tsuchida Tags: BJ Signal Source Type: research
LRRK2 Dephosphorylation increases its ubiquitination.
Activating mutations in the LRRK2 gene are the most common cause of inherited Parkinson’s disease (PD). LRRK2 is phosphorylated on a cluster of phosphosites including Ser910, 935, 955 and 973, which are dephosphorylated in several PD-related LRRK2 mutants [N1347H, R1441C/G, Y1699C and I2020T] linking the regulation of these sites to PD. These serine residues are also dephosphorylated after kinase inhibition and lose 14-3-3 binding, which serve as pharmacodynamic markers for inhibited LRRK2. Loss of 14-3-3 binding is well established, but the consequences of dephosphorylation are only now being uncovered. In the pres...
Source: BJ Disease - May 5, 2015 Category: Biochemistry Authors: J Zhao, T P Molitor, J Langston, R Nichols Tags: BJ Signal Source Type: research
Metabolomic profiling in liver of adiponectin knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action
In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2 to regulate lysophospholipid metabolism and ω-oxidation of fatty acids. (Source: BJ Disease)
Source: BJ Disease - April 27, 2015 Category: Biochemistry Authors: Y Liu, S Sen, S Wannaiampikul, R Palanivel, R L.C Hoo, R Isserlin, G D Bader, R Tungtrongchitr, Y Deshaies, A Xu, G Sweeney Tags: BJ Metabolism Source Type: research
Erythropoietin mediated expression of Placenta Growth Factor is regulated via activation of hypoxia inducible factor -1{alpha} and post-transcriptionally by mir214 in Sickle Cell Disease
Placental growth factor (PlGF) plays an important role in various pathological conditions and diseases such as inflammation, cancer, atherosclerosis and sickle cell disease (SCD). Abnormally high PlGF levels in SCD patients are associated with increased inflammation and pulmonary hypertension and reactive airway disease; however, the transcriptional and post-transcriptional mechanisms regulating PlGF expression are not well defined. Herein, we show that treatment of human erythroid cells and colony forming units with erythropoietin (EPO) increased PlGF expression. Our studies showed EPO mediated activation of HIF-1α...
Source: BJ Disease - April 16, 2015 Category: Biochemistry Authors: C S Gonsalves, C Li, M Eiymo Mwa Mpollo, V Pullarkat, P Malik, S M Tahara, V K Kalra Tags: BJ Disease Source Type: research
Loss of Conserved Gsdma3 Self-Regulation Causes Autophagy and Cell Death
Gsdermin A3 (Gsdma3) was originally identified for associating with hair-loss phenotype in mouse mutants. Our previous study found AE mutant mice, with a Y344H substitution at C-terminal domain of Gsdma3, display inflammation-dependent alopecia and excoriation. Interestingly, we found that the newly generated null mutant of Gsdma3 mice did not display the skin dysmorphology, indicating that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle innormal physiological conditions. Consistently, HEK293 and HaCaT cells transfected with wild-type Gsdma3 did not show abnormal morphology....
Source: BJ Disease - March 31, 2015 Category: Biochemistry Authors: P Shi, A Tang, L Xian, S Hou, D Zou, Y Lv, Z Huang, Q Wang, A Song, Z Lin, X Gao Tags: BJ Disease Source Type: research
Characterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1
In this study, we have characterized the interactions that are essential for SIVrcm Vpx-mediated degradation of rcmSAMHD1. Using mutagenesis and molecular modeling, we have determined the key role of the 23-WLHR-26 peptide of SIVrcm Vpx in recognizing rcmSAMHD1. The amino acids F15, L36, F52, R55 and R56 at the N-terminal region of rcmSAMHD1 are involved in interaction with Vpxrcm. The molecular model of the N-terminal region of rcmSAMHD1 (rcmSAMHD1-NtD), Vpxrcm and C-terminal region of DCAF1 (DCAF1-CtD) complex further reveals that rcmSAMHD1-NtD and Vpxrcm utilizes an interaction interface that is different from that used...
Source: BJ Disease - March 20, 2015 Category: Biochemistry Authors: J Li, F Xu, S Hu, J Zhou, S Mei, X Zhao, S Cen, Q Jin, C Liang, F Guo Tags: BJ Disease Source Type: research
Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain
Proteins of the echinoderm microtubule associated protein-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule (MT) network. EML1-4 consist of WD40 repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural...
Source: BJ Disease - March 5, 2015 Category: Biochemistry Authors: M W Richards, L O'Regan, D Roth, J M Montgomery, A Straube, A M Fry, R Bayliss Tags: BJ Biomolecules Source Type: research
Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity
Metformin is the mainstay therapy for type 2 diabetes (T2D), and many patients also take salicylate-based drugs (i.e. Aspirin; ASA) for cardioprotection. Metformin and salicylate both increase AMP-activated protein kinase (AMPK) activity but by distinct mechanisms, with metformin altering cellular adenylate charge (increasing AMP) and salicylate interacting directly at the AMPK β1 drug binding site. AMPK activation by both drugs results in phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme controlling fatty acid synthesis (lipogenesis). We find doses of metformin and salicylate ...
Source: BJ Disease - March 5, 2015 Category: Biochemistry Authors: R J Ford, M D Fullerton, S L Pinkosky, E A Day, J W Scott, J S Oakhill, A L Bujak, B K Smith, J D Crane, R M Blϋmer, K Marcinko, B E Kemp, H C Gerstein, G R Steinberg Tags: BJ Metabolism Source Type: research
An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein
A monoclonal antibody (mAb) that binds to a transient intermediate may act as a catalyst for the corresponding reaction; here we show this principle can extend on a macro-molecular scale to the induction of mutant-like oligomerisation in a wild-type protein. Using the common, pathogenic Glu342Lys (Z) variant of α1-antitrypsin as antigen - whose native state is susceptible to the formation of a proto-oligomeric intermediate - we have produced a mAb (5E3) that increases the rate of oligomerisation of the wild-type (M) variant. Employing ELISA, gel shift, thermal stability and FRET time-course experiments, we show that...
Source: BJ Disease - March 4, 2015 Category: Biochemistry Authors: J A Irving, E Miranda, I Haq, J Perez, V R Kotov, S V Faull, N Motamedi-Shad, D A Lomas Tags: BJ Biomolecules Source Type: research
Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: Functional Basis of P450 Oxidoreductase Deficiency
We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro.Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting flavin therapy may be useful for this frequent form of POR deficiency. Transient kinetic dissection of the reaction of POR with NADPH and the reduction of cytochrome c by POR using stopped-flow techniques reveale...
Source: BJ Disease - March 2, 2015 Category: Biochemistry Authors: Y Jin, M Chen, T M Penning, W L Miller Tags: BJ Disease Source Type: research
Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation.
Mutations in MT-ATP6 gene are frequent cause of severe mitochondrial disorders. Typically, these are missense mutations, but another type is represented by 9205delTA microdeletion, which removes the STOP codon of MT-ATP6 gene and affects the cleavage site in MT-ATP8/MT-ATP6/MT-CO3 polycistronic transcript. This interferes with the processing of mRNAs for Atp6 (Fo-a) subunit of ATP synthase and Cox3 subunit of cytochrome c oxidase (COX). Two cases described so far presented with strikingly different clinical phenotypes – mild transient lactic acidosis or fatal encephalopathy. To gain more insight into the pathogenic ...
Source: BJ Disease - January 15, 2015 Category: Biochemistry Authors: K Hejzlarová, V Kaplanová, H Nůsková, N Kovářová, P Ješina, Z Drahota, T Mráček, S Seneca, J Houstek Tags: BJ Disease Source Type: research
Molecular effects of cancer-associated somatic mutations on the structural and target recognition properties of Keap1
Kelch-like ECH-associated protein 1 (Keap1) plays an important regulatory role in the Nrf2-dependent oxidative stress response pathway. It functions as a repressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that initiates the expression of cytoprotective enzymes during oxidative stress to protect cells from damage caused by reactive oxygen species. Recent studies show that mutations of Keap1 can lead to aberrant activation of the antioxidant pathway, which is associated with different types of cancers. To gain a mechanistic understanding of the links between Keap1 mutations and cancer...
Source: BJ Disease - January 13, 2015 Category: Biochemistry Authors: H Khan, R Calvin Killoran, A Brickenden, J Fan, D Yang, W Choy Tags: BJ Biomolecules Source Type: research
{alpha}v{beta}6 Integrin Is Required for TGF{beta}1-Mediated Matrix Metalloproteinase2 Expression
TGFβ activity depends on a complex signaling cascade that controls expression of several genes. Among others, TGFβ1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. Here, we demonstrate for the first time that the αvβ6 integrin interacts with TGFβ receptor II (TβRII) through the β6 cytoplasmic domain and promotes Smad3 activation in prostate cancer cells. Another related αv integrin, αvβ5, as well as the αvβ6/3 integrin,which contains a chimeric form of β6 with a β3 cytoplasmic domain, do n...
Source: BJ Disease - January 6, 2015 Category: Biochemistry Authors: A Dutta, J Li, C Fedele, A Sayeed, A Singh, S M. Violette, T D. Manes, L R Languino Tags: BJ Signal Source Type: research
Expression of different bacterial cytotoxins is controlled by two global transcription factors, CRP and Fis, that cooperate in a shared-recruitment mechanism.
Pet is a cytotoxic autotransporter protein secreted by the pathogenic Enteroaggregative Escherichia coli strain 042. Expression of Pet is co-dependent on two global transcription regulators: CRP (cyclic AMP receptor protein) and Fis (factor for inversion stimulation). At the pet promoter CRP binds to a single site centred at position ‑40.5 upstream of the start site for transcription. Due to the suboptimal positioning of this site, CRP alone activates transcription poorly and requires Fis to bind upstream to promote full activation. Here, we show that CRP and Fis control the expression of other important autotranspo...
Source: BJ Disease - December 8, 2014 Category: Biochemistry Authors: A E Rossiter, R E Godfrey, J A Connolly, S J.W. Busby, I R Henderson, D F Browning Tags: BJ Gene Source Type: research
Cu2{+} accentuates distinct misfolding for A{beta}(1-40) and A{beta}(1-42) peptides, and potentiates membrane disruption
Central to Alzheimer’s Disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homeostasis is disrupted in the brains of sufferers of Alzheimer’s disease and causes heightened Alzheimer’s disease phenotype in animal models. Here we illustrate that substochiometric Cu2+ effects the misfolding pathway of Aβ(1-40), and the more toxic Aβ(1-42), in markedly different ways. Cu2+ accelerates Aβ(1-40) fibre formation, in contrast, for Aβ(1-42) substoichiometric levels...
Source: BJ Disease - December 4, 2014 Category: Biochemistry Authors: C J Matheou, N D Younan, J H Viles Tags: BJ Disease Source Type: research
