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)

The very different effects of Cholera Toxin (CT) on cell growth and proliferation may depend on the type of ganglioside receptors in cell membranes and different signal transduction mechanisms triggered, but other functions related to the drug resistance mechanisms can not be excluded. The effect of CT treatment on the "in vitro" clonogenicity, the Population Doubling Time (PDT), apoptosis, PKA activation and Bax and Bcl-2 expression was evaluated in WEHI-3B cell line and its CT-resistant subclone (WEHI-3B/CTRES). In WEHI-3B parental cells the dramatic accumulation of cAMP induced by CT correlated well with PKA activation, increased PDT value, inhibition of clonogenicity and apoptosis. H-89 treatment inhibited PKA activation by CT but did not protect the cells from apoptosis and growth inhibition. In WEHI-3B/CTRES no significant CT-dependent accumulation of cAMP occurred with any increase of PKA activity and PDT. In CT resistant cells (WEHI-3B/CTRES), Bcl-2 expression was down regulated by both CT or drug treatment (eg., ciprofloxacin, CPX) although these cells were protected from CT-dependent apoptosis but not from drug-induced apoptosis. Differently from other cell models described, down regulation of Bcl-2 is proved to be independent on cAMP accumulation and PKA activation. Our observations support the implication of cAMP dependent kinase (PKA) in the inhibition of WEHI-3B cells growth and suggest that, in WEHI-3B/CTRES, Bcl-2 expression could be modulated by CT in the absence of cAMP accumulation. Also in consideration of many contradictory data reported in literature, our cell models (of one sensitive parental cell strain and two clones with different uncrossed specific resistance to CT and CPX) provides a new and interesting tool for better investigating the relationship between the CT signal transduction mechanisms and Bcl-2 expression and function.
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PMID:Bcl-2 down modulation in WEHI-3B/CTRES cells resistant to Cholera Toxin (CT)-induced apoptosis. 1654 Nov 29

The involvement and potential interdependence of inositol trisphosphate (IP3) receptors and Bcl-2 in the regulation of Ca2+ signaling is not clear. Here, we have explored the mechanism(s) of how Bcl-2 suppresses the IP3-sensitive Ca2+ release in MCF-7 cells focusing on the possible role of protein phosphatase 1 (PP1). We found that through influences on protein-protein interaction, Bcl-2 may alter the balance between the effects of phosphatase (PP1) and kinase (PKA) on the IP3 R1 signaling complex. Using various experimental approaches including phosphatase inhibition and RNAi, we show that Bcl-2 by competing with IP3R1 for the binding of PP1 can reduce the IP3-mediated calcium signal and protect cells from mitochondrial dysfunction and cell death.
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PMID:Suppression of IP3-mediated calcium release and apoptosis by Bcl-2 involves the participation of protein phosphatase 1. 1687 61

AKAP12 (A-Kinase anchoring protein 12) is a protein kinase C substrate and a potential tumor suppressor. AKAP12 is down-regulated by several oncogenes and strongly suppressed in various cancers including prostate, ovarian and breast cancers. AKAP12 acts as a regulator of mitogenesis by anchoring key signal proteins such as PKA, PKC, and cyclins. In this study, AKAP12 was found to suppress tumor cell viability by inducing apoptosis via caspase-3 in HT1080 cells. This AKAP12-induced apoptosis was associated with a decreased expression of Bcl-2 and increased expression of Bax. Moreover, AKAP12-transfectant strongly induced the expression of Cip1/p21 and Kip1/p27, but resulted in a decrease in cyclin D1 involved in G(1) progression. Accordingly, these results suggest that AKAP12 may play an important role in tumor growth suppression by inducing apoptosis with the regulation of multiple molecules in the cell cycle progression.
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PMID:AKAP12 induces apoptotic cell death in human fibrosarcoma cells by regulating CDKI-cyclin D1 and caspase-3 activity. 1744 83

In the rodent cerebellum, PACAP is expressed by Purkinje neurons and PAC1 receptors are present on granule cells during both the development period and in adulthood. Treatment of granule neurons with PACAP inhibits proliferation, slows migration, promotes survival and induces differentiation. PACAP also protects cerebellar granule cells against the deleterious effects of neurotoxic agents. Most of the neurotrophic effects of PACAP are mediated through the cAMP/PKA signaling pathway and often involve the ERK MAPkinase. Caspase-3 is one of the key enzymes implicated in the neuroprotective action of PACAP but PACAP also inhibits caspase-9 activity and increases Bcl-2 expression. PACAP and functional PAC1 receptors are expressed in the monkey and human cerebellar cortex with a pattern of expression very similar to that described in rodents, suggesting that PACAP could also exert neurodevelopmental and neuroprotective functions in the cerebellum of primates including human.
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PMID:Neurotrophic effects of PACAP in the cerebellar cortex. 1754 70

The herpes simplex virus type 2 (HSV-2) protein ICP10PK has anti-apoptotic activity in virus-infected hippocampal cultures through activation of the Ras/Raf-1/MEK/ERK pathway. To exclude the possible contribution of other viral proteins to cell fate determination, we examined the survival of primary hippocampal cultures and neuronally differentiated PC12 cells transfected with ICP10PK from apoptosis caused by nerve growth factor (NGF) withdrawal. NGF deprivation caused apoptosis in cultures mock-transfected or transfected with the kinase-negative ICP10 mutant p139(TM), but not in ICP10PK-transfected cultures. In one clone (PC47), ICP10PK inhibited caspase-3 activation through up-regulation/stabilization of adenylate cyclase (AC), activation of PKA and MEK, and the convergence of the two pathways on extracellular signal-regulated kinase activation. The anti-apoptotic proteins Bag-1 and Bcl-2 were stabilized and the pro-apoptotic protein Bad was phosphorylated (inactivated). In another clone (PC70), ICP10PK inhibited apoptosis through MEK-dependent up-regulation of the anti-apoptotic protein XIAP (that inhibits the activity of processed caspase-3) and down-regulation of the apoptogenic protein Smac/DIABLO. This may be cell-type specific, but the baculovirus p35 protein did not potentiate the neuroprotective activity of ICP10PK in PC12 cells, suggesting that ICP10PK inhibits both caspase activation and activity. The data indicate that ICP10PK inhibits apoptosis independent of other viral proteins and is a promising neuronal gene therapy platform.
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PMID:The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation. 1787 40

H2O2, as an example of oxidative stress, induces cardiac myocyte apoptosis. Bcl-2 family proteins are key regulators of the apoptotic response while their functions can be regulated by post-translational modifications including phosphorylation, dimerization or proteolytic cleavage. In this study, we examined the role of various protein kinases in regulating total BAD protein levels in adult rat cardiac myocytes undergoing apoptosis. Stimulation with 0.1 mM H2O2, which induces apoptosis, resulted in a marked down-regulation of BAD protein, which is attributed to cleavage by caspases since it can be restored in the presence of a general caspase inhibitor. Inhibition of PKC, p38-MAPK, ERK1/2 and PI-3-K did not influence the reduced BAD protein levels observed after stimulation with H2O2. On the contrary, inhibition of PKA or specifically PKCdelta resulted in up-regulation of BAD. Decreased caspase 3 activity was observed in H2O2 treated cells after inhibition of PKA or PKCdelta whereas inhibition of PKA also resulted in improved cell survival. Furthermore, addition of okadaic acid to inhibit selected phosphatases resulted in enhanced BAD cleavage. These data suggest that, during oxidative stress-induced cardiac myocyte apoptosis, there is a caspase-dependent down-regulation of BAD protein, which seems to be regulated by coordinated action of PKA, PKCdelta and phosphatases.
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PMID:Regulation of BAD protein by PKA, PKCdelta and phosphatases in adult rat cardiac myocytes subjected to oxidative stress. 1797 75

Mitochondria, besides playing a central role in energy metabolism within the cell, are involved in a cohort of other processes like cellular differentiation and apoptosis. Investigations during recent few years have shown that protein kinases, including PKA, PKB/Akt, PKC, Raf-1, p38 MAPK, JNK, ERK1/2, Src, Fyn and Csk, may directly interact with mitochondrial proteins. Their role mainly concentrates at phosphorylation of pro- and anti-apoptotic proteins (Bad, Bax, Bcl-2, Bcl-xL), phosphorylation/modification of electron transport chain proteins (complex I, COIV), MPTP forming proteins VDAC and ANT, proteins of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) and phospholipid scramblase 3 (PLSCR3). Many experimental data showed the presence of protein kinases in the outer and inner mitochondrial membranes as well as in the mitochondrial matrix during in vitro cell stimulations, in neurodegenerative diseases and in in vivo ischaemia heart preconditioning. These data show that translocation of protein kinases to mitochondria plays an important role especially during ischaemia/reperfusion in brain and heart.
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PMID:[Protein kinases in mitochondria]. 1880 32

Neurodegeneration is a characteristic feature of AIDS dementia complex and is commonly associated with neuronal death in the brains of both pediatric and adult patients. Neuronal death associated with AIDS dementia complex can be induced by the HIV-1 protein gp120, but the underlying signal transduction mechanism remains unclear, especially for HIV-1 subtypes commonly seen in China. We have now demonstrated that the human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, appears to protect neuronal cultures through its ability to attenuate gp120-induced neuronal death. We found that (i) both pCREB levels and Bcl-2 expression are up-regulated in neuronal culture following treatment with CCL3L1 plus gp120; (ii) CCL3L1 induces cell survival via phosphorylation of CREB by way of the PKA and CaMKI/CaMKIV cell signaling pathways; (iii) transcription of the cell survival gene bcl-2 is induced by pCREB; and (iv) CCL3L1 protects cultured neurons against CCR5-mediated excitotoxicity induced by gp120. Thus, the CCL3L1/bcl-2-regulated anti-apoptotic pathway significantly contributes to reduction of HIV-1/gp120-induced neuronal apoptosis, and therefore, CCL3L1 should be further investigated as a potential chemokine to protect against neuronal injury in gp120-related neuronal toxicity.
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PMID:CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathway. 1910 Jul 22

Latent membrane protein-1 (LMP-1) of the Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC), and in this study we sought to determine whether the pro-apoptotic activity of prostate apoptosis response-4 (Par-4) is modulated by LMP-1 in NPC cells. We found that LMP-1 diminished the pro-apoptotic activity of Par-4 and negatively regulated Par-4 protein by de novo synthesis; moreover, although LMP-1 accelerated a Par-4 activator, PKA, we demonstrated that LMP-1 also activated the PI3K/Akt pathway and increased Bcl-2 expression to suppress the activity of Par-4. Consequently, our results revealed a novel negative action of LMP-1 on the pro-apoptosis protein Par-4 by the coordination of multiple signaling pathways.
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PMID:EBV LMP-1 negatively regulates expression and pro-apoptotic activity of Par-4 in nasopharyngeal carcinoma cells. 1925 Jul 35

Previously, we reported that the catalytic subunit of cAMP-dependent protein kinase (PKAc) binds to the active p90 ribosomal S6 kinase 1 (RSK1) (Chaturvedi, D., Poppleton, H. M., Stringfield, T., Barbier, A., and Patel, T. B. (2006) Mol. Cell. Biol. 26, 4586-4600). Herein, by overexpressing hemagglutinin-tagged RSK1 fragments in HeLa cells we have identified the region of RSK1 that is responsible for the interaction with PKAc. PKAc bound to the last 13 amino acids of RSK1, which overlaps the Erk1/2 docking site. This interaction between PKAc and RSK1 required the phosphorylation of Ser-732 in the C terminus of RSK1. Depending upon its phosphorylation status, RSK1 switched interactions between Erk1/2 and PKAc. In addition, a peptide corresponding to the last 13 amino acids of RSK1 with substitution of Ser-732 with Glu (peptide E), but not Ala (peptide A), decreased interactions between endogenous active RSK1 and PKAc. RSK1 attenuated the ability of cAMP to activate PKA in vitro and this modulation was abrogated by peptide E, but not by peptide A. Similarly, in intact cells, cAMP-mediated phosphorylation of Bcl-xL/Bcl-2-associated death promoter on Ser-115, the PKA site, was reduced when RSK1 was activated by epidermal growth factor, and this effect was blocked by peptide E, but not by peptide A. These findings demonstrate that interactions between endogenous RSK1 and PKAc in intact cells regulate the ability of cAMP to activate PKA and identify a novel mechanism by which PKA activity is regulated by the Erk1/2 pathway.
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PMID:Regulation of protein kinase A activity by p90 ribosomal S6 kinase 1. 1980 66


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