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)

We previously reported that senescent human diploid fibroblasts (HDFs) are resistant to apoptosis induced by H(2)O(2) and staurosporine. We report here that senescent HDFs are resistant to thapsigargin-induced apoptosis as well. These agonists caused the reductions in mitochondrial membrane potential (MMP) and in the apoptosis inhibitory protein (B-cell lymphoma) only in young HDFs but not in senescent HDFs. In addition, downregulation of Bcl-2 increased the sensitivity of senescent HDFs to apoptosis induction, suggesting the significant role of Bcl-2 in apoptosis resistance of the senescent HDFs. We further found that P-cAMP response element-binding protein (CREB), a positive regulator of Bcl-2, decreased in stress-induced apoptosis of young HDFs but not in senescent HDFs, and that Bcl-2 was markedly reduced in CREB small interfering RNA (siRNA), transfected senescent HDFs. In addition, activity of protein phosphatase 2A (PP2A), which dephosphorylates p-CREB, significantly increased in young HDFs but not in senescent HDFs treated with H(2)O(2), staurosporine or thapsigargin. Taken together, these results suggest that failure of stress-induced downregulation of Bcl-2 underlies resistance of senescent HDFs to apoptosis.
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PMID:Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts. 1729 Feb 86

Cerebral ischemia triggers robust phosphorylation of cAMP response element-binding protein (CREB) and CRE-mediated gene expression in neurons. Glutamate receptor activation and subsequent calcium influx may activate CREB shortly after ischemia. CREB activation leads to expression of genes encoding neuroprotective molecules, such as the antiapoptotic protein Bcl-2, and contributes to survival of neurons after ischemic insult. Recent studies have suggested that CREB may be involved in acquisition of ischemic tolerance, a phenomenon that occurs after sublethal ischemic stress. CREB activation is also involved in the survival of newborn neurons in the dentate gyrus of the hippocampus after ischemia. Therefore, CREB-related therapeutics may be promising for brain protection and endogenous neurogenesis and could promote functional recovery in ischemic stroke patients. This minireview summarizes our current understanding for the role of CREB in regulating CRE-mediated gene expression during cerebral ischemia.
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PMID:CREB and cAMP response element-mediated gene expression in the ischemic brain. 1756 98

1,2-Naphthoquinone (1,2-NQ) is an atmospheric contaminant with electrophilic properties that allow it to react readily with protein thiol groups such as those found on the cAMP response element-binding protein (CREB), a transcription factor with conserved cysteine residues that regulate DNA binding. In the present study, we explored the possibility that the interaction of 1,2-NQ with CREB will affect its activity, resulting in down-regulation of gene expression. With bovine aortic endothelial cells (BAECs) and a cell-free system, 1,2-NQ was found to covalently bind to CREB, and inhibit its DNA binding activity under conditions that were blocked by dithiothreitol. CRE-dependent luciferase activity and the down-regulation of Bcl-2 expression were suppressed by exposure of BAECs to 1,2-NQ. This phenomenon was not seen with the hydrocarbon, naphthalene, which lacks any electrophilic properties. The results indicate that CREB is a molecular target for 1,2-NQ which through irreversible binding, inhibits the function of this transcription factor.
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PMID:1,2-Naphthoquinone disrupts the function of cAMP response element-binding protein through covalent modification. 1765 70

Microbial products, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DCs) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulin-dependent kinase IV (CaMKIV) in this survival program. The pharmacologic inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decrease the viability of monocyte-derived DCs exposed to bacterial LPS. The defect in TLR4 signaling includes a failure to accumulate the phosphorylated form of the cAMP response element-binding protein (pCREB), Bcl-2, and Bcl-xL. CaMKIV null mice have a decreased number of DCs in lymphoid tissues and fail to accumulate mature DCs in spleen on in vivo exposure to LPS. Although isolated Camk4-/- DCs are able to acquire the phenotype typical of mature cells and release normal amounts of cytokines in response to LPS, they fail to accumulate pCREB, Bcl-2, and Bcl-xL and therefore do not survive. The transgenic expression of Bcl-2 in CaMKIV null mice results in full recovery of DC survival in response to LPS. These results reveal a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival.
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PMID:Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells. 1790 78

Many growth regulatory stimuli promote cAMP response element-binding protein (CREB) Ser(133) phosphorylation, but the physiologically relevant CREB-Ser(133) kinase(s) in the heart remains uncertain. This study identifies a novel role for protein kinase D (PKD) as an in vivo cardiac CREB-Ser(133) kinase. We show that thrombin activates a PKCdelta-PKD pathway leading to CREB-Ser(133) phosphorylation in cardiomyocytes and cardiac fibroblasts. alpha(1)-Adrenergic receptors also activate a PKCdelta-PKD-CREB-Ser(133) phosphorylation pathway in cardiomyocytes. Of note, while the epidermal growth factor (EGF) promotes CREB-Ser(133) phosphorylation via an ERK-RSK pathway in cardiac fibroblasts, the thrombin-dependent EGFR transactivation pathway leading to ERK-RSK activation does not lead to CREB-Ser(133) phosphorylation in this cell type. Adenoviral-mediated overexpression of PKCdelta (but not PKCepsilon or PKCalpha) activates PKD; PKCdelta and PKD1-S744E/S748E overexpression both promote CREB-Ser(133) phosphorylation. Pasteuralla multocida toxin (PMT), a direct Galpha(q) agonist that induces robust cardiomyocyte hypertrophy, also activates the PKD-CREB-Ser(133) phosphorylation pathway, leading to the accumulation of active PKD and Ser(133)-phosphorylated CREB in the nucleus, activation of a CRE-responsive promoter, and increased Bcl-2 (CREB target gene) expression in cardiomyocyte cultures. Cardiac-specific Galpha(q) overexpression also leads to an increase in PKD-Ser(744)/Ser(748) and CREB-Ser(133) phosphorylation as well as increased Bcl-2 protein expression in the hearts of transgenic mice. Collectively, these studies identify a novel Galpha(q)-PKCdelta-PKD-CREB-Ser(133) phosphorylation pathway that is predicted to contribute to cardiac remodeling and could be targeted for therapeutic advantage in the setting of heart failure phenotypes.
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PMID:Protein kinase D links Gq-coupled receptors to cAMP response element-binding protein (CREB)-Ser133 phosphorylation in the heart. 1837 85

The extracellular signal-regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase that phosphorylates and regulates various transcription factors in response to growth factors and extracellular stresses. To address its biological function during the development of the peripheral nervous system (PNS), we have engineered a novel model of sympathetic neurons in which the erk5 gene can be deleted in vitro. Our data provide for the first time genetic evidence that ERK5 is required to mediate the survival response of neurons to nerve growth factor. Increased cell death associated with the loss of ERK5 is caused by elevated expression of the BH3-only members of the Bcl-2 family, Bad and Bim. Further investigation indicated that ERK5 suppresses the transcription of the bad and the bim genes by Ca(2+)/cAMP response element-binding protein and Forkhead box O3a, respectively. Consistently, we found that the phosphorylation of both p90 ribosomal S6 kinase and protein kinase B is impaired in neurons lacking ERK5. Together these findings reveal a novel signaling mechanism that promotes neuronal survival during the development of the PNS.
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PMID:Regulation of neuronal survival by the extracellular signal-regulated protein kinase 5. 1914 85

Ischemic preconditioning (IP) is a defense program in which exposure to sublethal ischemia followed by a period of reperfusion results in subsequent resistance to severe ischemic insults. Very few in vivo IP models have been established for neonatal brain. We examined whether rapid, intermediate, and delayed IP against hypoxic-ischemia (HI) could be induced in neonatal brain, and if so, whether the IP involved phosphorylation of cAMP response element-binding protein (pCREB) after HI. Postnatal day 7 rat pups were subjected to HI at 2 h (2-h IP), 6 h (6-h IP), or 22 h (22-h IP) after IP. We found all three IP groups had significantly reduced neuronal damage and TUNEL-(+) cells 24 h post-HI than no-IP group. Compared with control, the no-IP group had significant decreases of pCREB and mitochondria Bcl-2 levels in the ipsilateral cortex 24 h post-HI. In contrast, the three IP groups had increased pCREB and mitochondria Bcl-2 levels, and significant differences were found between three IP and no-IP groups. The increases of cleavage of caspase-3 and poly (ADP-ribose) polymerase and of cells with nuclear apoptosis inducing factor post-HI in no-IP group were all significantly reduced in three IP groups. The increases of caspase-3 and calpain-mediated proteolysis of a-spectrin post-HI were significantly reduced only in 22-h IP group. Furthermore, all three IP groups had long-term neuroprotection at behavioral and pathological levels compared with no-IP group. In conclusion, IP, rapid, intermediate, or delayed, in neonatal rat brain activates CREB, up-regulates Bcl-2, induces extensive brakes on caspase-dependent and -independent apoptosis after HI, and provides long-term neuroprotection.
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PMID:CREB activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat. 1918 66

Extracellular signal-regulated kinases (ERKs) are widely implicated in multiple physiological processes. Although ERK1/2 has been proposed as a common mediator of antidepressant action in naive rodents, it remains to be determined whether the ERK1/2 pathway plays a role in depressive disorder. Here, we investigated whether chronic restraint stress (14 days) and antidepressant treatment [desipramine (DMI), 10 mg/kg intraperitoneally] induce changes in animal behavior and hippocampal levels of phospho-ERK1/2 and its substrate phospho-cAMP response element-binding protein (CREB). The results indicated that stress-induced depressive-like behaviors were correlated with an increase in P-ERK1/2 and P-CREB in the hippocampus evaluated by immunoblot analysis. As an indication of CREB activity, we evaluated changes in mRNA levels of its target genes. Brain-derived neurotrophic factor (BDNF) mRNA was reduced by stress, an effect prevented by DMI only in the CA3 area of hippocampus. Bcl-2 mRNA was reduced in all hippocampal regions by stress, an effect independent of DMI treatment. However, immunoblot from hippocampal extracts revealed that stress increased BCL-2 levels, an effect prevented by chronic DMI. These results suggest that ERKs and BDNF may be altered in depressive disorder, modifications that are sensitive to DMI action. In contrast, the stress-induced increase in BCL-2 may correspond to a neuroprotective response.
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PMID:Desipramine prevents stress-induced changes in depressive-like behavior and hippocampal markers of neuroprotection. 1942 57

Protein kinase C epsilon (PKCepsilon) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKCepsilon in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl-2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKCepsilon in breast cancer cells. siRNA silencing of either PKCepsilon or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKCepsilon, but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKCepsilon but contain little constitutively-active Akt. Knockdown of PKCepsilon decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCepsilon regulates Bcl-2 induction through activation of the transcription factor CREB.
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PMID:PKCepsilon induces Bcl-2 by activating CREB. 2019 32

Cardiomyocyte apoptosis plays a critical role in the progress of heart diseases. Asperosaponin VI (ASA VI), a triterpene saponin isolated from Dipsacus asper Wall, has shown cardioprotective effects in vivo. However, whether ASA VI has a protective effect against cardiomyocyte apoptosis is poorly understood. The present study was aimed to investigate the cardioprotective role of ASA VI and the underlying mechanisms in hypoxia-induced cardiomyocyte apoptosis. Cardiomyocytes were exposed to hypoxic condition for 6 h and then cell viability markedly decreased, lactate dehydrogenase (LDH) and creatine phosphokinase (CK) activities in the culture supernatant significantly increased. Hypoxia-activated apoptosis were confirmed by Hoechst 33258 nuclear staining and Annexin V-FITC staining. These changes were associated with the decrease of the Bcl-2/Bax ratio, active caspase-3 expression, phosphorylations of Akt and cAMP response element-binding protein (CREB). Moreover, ASA VI significantly attenuated increased LDH and CK activities, and increased cell viability in hypoxia treated myocytes in a dose-dependent fashion. Hoechst 33258 nuclear staining and Annexin V-FITC staining observations demonstrated the same protective effects. ASA VI treatment inhibited apoptosis in hypoxia-induced cardiomyocyte by increasing the Bcl-2/Bax ratio and decreasing active caspase-3 expression, as well as enhancing of p-Akt and p-CREB. Furthermore, the protective effects of ASA VI were prevented by phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 treatment. In consequence, we demonstrated that ASA VI had protective effect against hypoxia-induced cardiomyocytes apoptosis probably by activating the PI3K/Akt and CREB pathways.
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PMID:Asperosaponin VI protects cardiac myocytes from hypoxia-induced apoptosis via activation of the PI3K/Akt and CREB pathways. 2086 24


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