Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3beta (GSK-3beta) is a critical activator of neuronal apoptosis induced by a diverse array of neurotoxic insults. However, the downstream substrates of GSK-3beta that ultimately induce neuronal death are unknown. Here, we show that GSK-3beta phosphorylates and regulates the activity of Bax, a pro-apoptotic Bcl-2 family member that stimulates the intrinsic (mitochondrial) death pathway by eliciting cytochrome c release from mitochondria. In cerebellar granule neurons undergoing apoptosis, inhibition of GSK-3beta suppressed both the mitochondrial translocation of an expressed green fluorescent protein (GFP)-Bax(alpha) fusion protein and the conformational activation of endogenous Bax. GSK-3beta directly phosphorylated Bax(alpha) on Ser163, a residue found within a species-conserved, putative GSK-3beta phosphorylation motif. Coexpression of GFP-Bax(alpha) with a constitutively active mutant of GSK-3beta, GSK-3beta(Ser9Ala), enhanced the in vivo phosphorylation of wild-type Bax(alpha), but not a Ser163Ala mutant of Bax(alpha), in transfected human embryonic kidney 293 (HEK293) cells. Moreover, cotransfection with constitutively active GSK-3beta promoted the localization of Bax(alpha) to mitochondria and induced apoptosis in both transfected HEK293 cells and cerebellar granule neurons. In contrast, neither a Ser163Ala point mutant of Bax(alpha) nor a naturally occurring splice variant that lacks 13 amino acids encompassing Ser163 (Bax(sigma)) were driven to mitochondria in HEK293 cells coexpressing constitutively active GSK-3beta. In a similar manner, either mutation or deletion of the identified GSK-3beta phosphorylation motif prevented the localization of Bax to mitochondria in cerebellar granule neurons undergoing apoptosis. Our results indicate that GSK-3beta exerts some of its pro-apoptotic effects in neurons by regulating the mitochondrial localization of Bax, a key component of the intrinsic apoptotic cascade.
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PMID:Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. 1552 85

Adrenomedullin (AM) has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of delayed AM gene transfer in cerebral ischemia. Three days after a 1-hr occlusion of the middle cerebral artery (MCAO), rats were injected intravenously with adenovirus harboring human AM cDNA. The experiment was terminated 7 days after MCAO. AM gene transfer significantly reduced cerebral infarct size compared with that of rats before virus injection and compared with that of rats injected with control virus. The expression of recombinant human AM was identified in ischemic brain by immunostaining. Morphological analyses showed that AM gene transfer enhanced the survival and migration of astrocytes into the ischemic core. Cerebral ischemia markedly increased astrocyte apoptosis, and AM gene delivery significantly reduced apoptosis to near normal levels as seen in sham control rats. Similarly, in primary cultured astrocytes, AM stimulated cell migration and inhibited hypoxia/reoxygenation-induced apoptosis. The effects of AM on both migration and apoptosis were abolished by calcitonin gene-related peptide [CGRP(8-37)], an AM receptor antagonist. Enhanced cell survival after AM gene transfer was accompanied by markedly increased cerebral nitric oxide and Bcl-2 levels, as well as Akt and GSK-3beta phosphorylation, but reduced NADPH oxidase activity and superoxide production. Inactivation of GSK-3beta by phosphorylation led to reduced GSK-3beta activity and caspase- 3 activation. These results indicate that exogenous AM provides neuroprotection against cerebral ischemia injury by enhancing astrocyte survival and migration and inhibiting apoptosis through suppression of oxidative stress-mediated signaling events.
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PMID:Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. 1568

Gamma-catenin is a cell adhesion molecule and a candidate mediator of Wnt signal transduction. We hypothesized that impaired regulation of gamma-catenin through genetic and epigenetic pathways is associated with the pathogenesis of prostate cancer. To test this hypothesis, cytosine-phosphate-guanine methylation, loss of heterozygosity (LOH), and mutation status of the gamma-catenin gene were analyzed in cultured prostate cancer cell lines, 180 localized prostate cancers, 69 benign prostatic hyperplasias, and 11 hormone refractory prostate cancers (HRPC). In prostate cancer cell lines (DuPro, LNCaP, ND-1, and PC3), gamma-catenin mRNA transcripts were increased after 5-aza-2'-deoxycytidine treatment. In localized prostate cancer, gamma-catenin expression was lower but prevalence of gamma-catenin methylation was higher compared with benign prostatic hyperplasia. However, gamma-catenin methylation did not correlate with Gleason sum, pT category, or capsular penetration. Among localized prostate cancers with positive gamma-catenin methylation, the presence of LOH at chromosome 17q21 was closely related to down-regulation of gamma-catenin mRNA expression. The gamma-catenin mutations were not found in localized prostate cancers, whereas six mutations were found in five HRPCs within or close to the GSK-3beta consensus motif phosphorylation site, among which four HRPCs showed strong nuclear gamma-catenin accumulation. In these four HRPCs, Bcl-2 expression was increased, whereas the target of the Wnt signal, c-myc, was only expressed in one HRPC. Therefore, although epigenetic gamma-catenin methylation is an early event in the development of prostate cancer, simultaneous events of epigenetic cytosine-phosphate-guanine methylation and genetic LOH may be responsible for functional loss of gamma-catenin. The gamma-catenin mutation related to Bcl-2 overexpression has a significant effect on the pathogenesis of HRPC. This is the first report to characterize the epigenetic and genetic regulation of gamma-catenin in human prostate cancer.
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PMID:Functional Loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer. 1578 23

Genetic studies in humans and mice have revealed an important role of the Wnt signaling pathway in the regulation of bone mass, resulting from potent effects on the control of osteoblast progenitor proliferation, commitment, differentiation, and perhaps osteoblast apoptosis. To establish the linkage between Wnts and osteoblast survival and to elucidate the molecular pathways that link the two, we have utilized three cell models: the uncommitted bipotential C2C12 cells, the pre-osteoblastic cell line MC3T3-E1, and bone marrow-derived OB-6 osteoblasts. Serum withdrawal-induced apoptosis was prevented by the canonical Wnts (Wnt3a and Wnt1) and the noncanonical Wnt5a in all cell types. Wnt3a induced LRP5-independent transient phosphorylation and nuclear accumulation of ERKs and phosphorylation of Src and Akt. The anti-apoptotic effect of Wnt3a was abrogated by inhibitors of canonical Wnt signaling, as well as by inhibitors of MEK, Src, phosphatidylinositol 3-kinase (PI3K), or Akt kinases, or by the addition of cycloheximide to the culture medium. Wnt3a-induced phosphorylation of GSK-3beta and downstream activation of beta-catenin-mediated transcription required ERK, PI3K, and Akt signaling. Wnt3a increased the expression of the anti-apoptotic protein Bcl-2 in an ERK-dependent manner. Beta-catenin-mediated transcription was permissive for the anti-apoptotic actions of Wnt1 and Wnt3a but was dispensable for the anti-apoptotic action of Wnt5a. However, Src, ERKs, PI3K, and Akt kinases were required for the anti-apoptotic effects of Wnt5a. These results demonstrate for the first time that Wnt proteins, irrespective of their ability to stimulate canonical Wnt signaling, prolong the survival of osteoblasts and uncommitted osteoblast progenitors via activation of the Src/ERK and PI3K/Akt signaling cascades.
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PMID:Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT. 1625 Nov 84

Ischemic preconditioning (IP) enhances vascular endothelial growth factor (VEGF), Bcl-2 and survivin expression after myocardial infarction (MI). Mechanisms of angiogenic and anti-apoptotic effects due to IP still remain unclear. The present study attempts to address whether GSK-3beta-beta-catenin signaling in turn interacts with T-cell transcription factor/lymphoid-enhancer binding factor (TCF/LEF) and regulates these genes in the ischemic preconditioned myocardium. In a rat MI model with permanent occlusion of left anterior descending coronary artery (LAD), IP (four cycles of 4-min of ischemia and 4-min of reperfusion) significantly phosphorylated and inhibited GSK-3beta and accumulated beta-catenin in the cytosol and nucleus. Wortmannin, a PI-3 kinase inhibitor, repressed this effect in our model. We examined whether pretreatment with GSK-3beta inhibitor lithium or SB216763, mimicked IP-mediated angiogenesis and cardioprotection. Lithium- or SB216763- treated rats revealed accumulation of cytosolic and nuclear beta-catenin. This was followed by increased TCF/LEF transcriptional activity and the upregulation of VEGF, Bcl-2 and survivin mRNA expression accompanied by reduction of apoptotic cardiomyocytes and endothelial cells and increased capillary density after MI. The results of this study demonstrate, first time that inhibition of GSK-3beta followed by accumulation of beta-catenin in the cytosol and nucleus has potent anti-apoptotic and angiogenic effects after MI and that the PI3-kinase/GSK-3beta/beta-catenin signaling pathway plays an important role in IP.
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PMID:Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. 1628 8

Activation of the high-affinity IgE-receptor, FcepsilonRI, expressed on mast cells can result in either enhanced survival or apoptosis depending on the circumstances. In this study, we have analysed signalling pathways involved in the regulation of mast cell survival and apoptosis. FcepsilonRI cross-linking induces phosphorylation of Akt and its downstream target forkhead transcription factors. In addition, Bad, GSK-3beta and IkappaB-alpha also become phosphorylated. A1, a prosurvival Bcl-2 homologue transcriptionally controlled by NFkappaB transcription factors, is upregulated upon FcepsilonRI activation. These events have prosurvival effects on the mast cells. Moreover, FcepsilonRI activation upregulates the levels of the proapoptotic protein Bim and induces a rapid, but transient, phosphorylation of Bim. Thus, FcepsilonRI activation of mast cells leads to both prosurvival and proapoptotic signalling events where the outcome most likely depends on the balance between these signals.
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PMID:IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members. 1639 95

Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes. However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of "hypertrophic" markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and "hypertrophic" marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3beta to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model.
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PMID:Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. 1651 74

Glycogen synthase kinase-3 (GSK-3) has recently been identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury (SCI) in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a potent and selective GSK-3beta inhibitor, significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase activity); 3) inducible nitric-oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression; and 4) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Bax and Bcl-2 expression). In a separate set of experiments, TDZD-8 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with TDZD-8 reduces the development of inflammation and tissue injury associated with spinal cord trauma.
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PMID:Glycogen synthase kinase-3 beta inhibition reduces secondary damage in experimental spinal cord trauma. 1660 Nov 44

Despite much evidence that lithium and valproate, two commonly used mood stabilizers, exhibit neuroprotective properties against an array of insults, the pharmacological relevance of such effects is not clear because most of these studies examined the acute effect of these drugs in supratherapeutic doses against insults which were of limited disease relevance to bipolar disorder. In the present study, we investigated whether lithium and valproate, at clinically relevant doses, protects human neuroblastoma (SH-SY5Y) and glioma (SVG and U87) cells against oxidative stress and endoplasmic reticulum stress in a time-dependent manner. Pretreatment of SH-SY5Y cells for 7 days, but not 1 day, with 1 mM of lithium or 0.6 mM of valproate significantly reduced rotenone and H2O2-induced cytotoxicity, cytochrome c release and caspase-3 activation, and increased Bcl-2 levels. Conversely, neither acute nor chronic treatment of SH-SY5Y cells with lithium or valproate elicited cytoprotective responses against thapsigargin-evoked cell death and caspase-3 activation. Moreover, inhibitors of glycogen synthase kinase-3 (GSK-3), kenpaullone and SB216763, abrogated rotenone-induced, but not H2O2-induced, cytotoxicity. Thus the cytoprotective effects of lithium and valproate against H2O2-induced cell death is likely independent of GSK-3 inhibition. On the other hand, chronic lithium or valproate treatment did not ameliorate cytotoxicity induced by rotenone, H2O2, and thapsigargin in SVG astroglial and U87 MG glioma cell lines. Our results suggest that lithium and valproate may decrease vulnerability of human neural, but not glial, cells to cellular injury evoked by oxidative stress possibly arising from putative mitochondrial disturbances implicated in bipolar disorder.
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PMID:Cytoprotection by lithium and valproate varies between cell types and cellular stresses. 1667 57

Interleukin (IL)-5 is a hematopoietic cytokine able to regulate differentiation, survival, and effector functions of eosinophils. It binds specifically to its receptor, which is composed of a cytokine-specific alpha-chain and a beta-chain shared with the receptors for IL-3 and the granulocyte macrophage-colony stimulating factor. The molecular mechanisms by which IL-5 modulates eosinophil survival remain unclear. In this study, we demonstrate that IL-5 withdrawal induces eosinophil apoptosis through a mitochondria-dependent pathway, independently of Fas receptor activation. The lipid kinase phosphatidylinositol-3 kinase plays a crucial role in the maintenance of eosinophil survival, as inhibition of its activity results in apoptosis. IL-5 induces phosphorylation and thus, inhibition of the Forkhead transcription factor FOXO3a and glycogen synthase kinase 3 (GSK-3). We analyzed expression of FOXO3a-dependent transcriptional targets: Fas ligand or Bim (a proapoptotic Bcl-2 family member), but neither was detected in apoptotic eosinophils. We further show that GSK-3 is activated after IL-5 withdrawal, and inhibition of its activity rescues eosinophils from apoptosis. beta-catenin, a direct GSK-3 substrate, is present in the nucleus of IL-5-stimulated eosinophils, but it is translocated to the plasma membrane in the absence of cytokine in a GSK-3-dependent manner. This is the first report describing a potential role for GSK-3 and beta-catenin in regulating eosinophil survival and suggests a novel mechanism by which IL-5 inhibits the constitutive apoptotic program in these cells.
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PMID:IL-5-mediated eosinophil survival requires inhibition of GSK-3 and correlates with beta-catenin relocalization. 1668 89


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