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

Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.
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PMID:CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells. 1920 32

The immunosuppressant cyclosporine A (CsA) is a specific pharmacological inhibitor of calcineurin, the Ca2+-calmodulin activated phospho-Ser/Thr-specific protein phosphatase. Although calcineurin-inhibiting compounds are applied for local treatment of psoriasis or atopic dermatitis in dermatological practice, little is known about the functions of calcineurin in epidermis-derived malignancies. We investigated the effects of CsA on two human melanoma cell lines, the metastasis forming HT168 and WM35 established from an RGP primary lesion. CsA of 2 microM lowered the enzyme activity by 50% and caused elevation in both mRNA and protein expression of calcineurin. Cell proliferation was diminished, as well as the cellular morphology and the actin organization were altered in both cell lines. CsA increased cell death moderately in both cell lines and reduced the metabolic activity of HT168 cells, but not that of WM35 cells. CsA also elevated the expressions of both Bcl-2 and ERK1/2. Fibronectin guided migration of HT168 cells was stimulated under the effect of CsA, while that of WM35 cells was reduced, moreover, HT168 cells switched from the expression of beta3 to beta1 integrin, but WM35 cells continued to express beta3. Based on our results we propose a multiple, partly malignancy-dependent role of calcineurin in these melanoma cell lines.
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PMID:Inhibition of calcineurin by cyclosporine A exerts multiple effects on human melanoma cell lines HT168 and WM35. 1928 56

Previous reports have shown that various steps in the influenza A virus life cycle are impaired in cells expressing the antiapoptotic protein Bcl-2 (Bcl-2(+) cells). We demonstrated a direct link between Bcl-2 and the reduced nuclear export of viral ribonucleoprotein (vRNP) complexes in these cells. However, despite its negative impact on viral replication, Bcl-2 did not prevent host cells from undergoing virally triggered apoptosis. The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38MAPK. In infected Bcl-2(+) cells, activated p38MAPK was found predominantly in the cytoplasm, colocalized with Bcl-2, and both Bcl-2 phosphorylation and virally induced apoptosis were diminished by specific inhibition of p38MAPK activity. In contrast, in Bcl-2-negative (Bcl-2(-)) cells, which are fully permissive to viral infection, p38MAPK activity was predominantly nuclear, and its inhibition decreased vRNP traffic, phosphorylation of viral nucleoprotein, and virus titers in cell supernatants, suggesting that this kinase also contributes to the regulation of vRNP export and viral replication. This could explain why in Bcl-2(+) cells, where p38MAPK is active in the cytoplasm, phosphorylating Bcl-2, influenza viral replication is substantially reduced, whereas apoptosis proceeds at rates similar to those observed in Bcl-2(-) cells. Our findings suggest that the impact of p38MAPK on the influenza virus life cycle and the apoptotic response of host cells to infection depends on whether or not the cells express Bcl-2, highlighting the possibility that the pathological effects of the virus are partly determined by the cell type it targets.
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PMID:Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: impact on virally induced apoptosis and viral replication. 1933 99

The extracellular signal-regulated kinases 1/2 (ERK1/2) are serine/threonine-selective protein kinases involved in proliferation and differentiation of cells, including thymocytes. The requirement of ERK1/2 for thymocyte differentiation and maturation has been well established; however, their role in regulating thymocyte survival and apoptosis has not been resolved. Here, we asked whether ERK1/2 affected thymocyte survival in vitro in response to apoptotic stimuli. The results show that phorbol 12-myristate 13-acetate (PMA) treatment (with or without ionomycin) and serum starvation (s/s) induced sustained ERK1/2 activation in murine thymocytes. Importantly, pharmacological treatment of thymocytes with the MEK inhibitor UO126 revealed that PMA-induced ERK1/2 activation was proapoptotic, whereas serum starvation-induced ERK1/2 activation inhibited apoptosis and promoted cell survival. While basal MEK activity was required for both s/s- and PMA-induced ERK1/2 activation, MEK activity increased only in response to PMA. The results show that the suppression of ERK1/2 phosphatases was responsible for s/s-induced sustained ERK1/2 activation. Unexpectedly, neither s/s-induced proapoptotic nor PMA-induced anti-apoptotic functions of ERK1/2 depended on the Bcl-2 family phosphoprotein Bim(EL), which was previously implicated in thymocyte apoptosis. Lastly, etoposide treatment of immature thymocytes induced both p53 and ERK1/2 activation, but ERK1/2 activity did not affect the phosphorylation and stabilization of p53. Thus, ERK1/2 has a dual role in promoting cell survival and cell death in thymocytes in the context of different stimuli.
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PMID:Prosurvival and proapoptotic functions of ERK1/2 activation in murine thymocytes in vitro. 1991 7

Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) plays an important role mediating apoptosis/necrosis during ischemia-reperfusion (IR). We explored the mechanisms of this deleterious effect. Langendorff perfused rat and transgenic mice hearts with CaMKII inhibition targeted to sarcoplasmic reticulum (SR-AIP) were subjected to global IR. The onset of reperfusion increased the phosphorylation of Thr(17) site of phospholamban, without changes in total protein, consistent with an increase in CaMKII activity. Instead, there was a proportional decrease in the phosphorylation of Ser2815 site of ryanodine receptors (RyR2) and the amount of RyR2 at the onset of reperfusion, i.e. the ratio Ser2815/RyR2 did not change. Inhibition of the reverse Na(+)/Ca(2+)exchanger (NCX) mode (KBR7943) diminished phospholamban phosphorylation, reduced apoptosis/necrosis and enhanced mechanical recovery. CaMKII-inhibition (KN-93), significantly decreased phospholamban phosphorylation, infarct area, lactate dehydrogenase release (LDH) (necrosis), TUNEL positive nuclei, caspase-3 activity, Bax/Bcl-2 ratio and Ca(2+)-induced mitochondrial swelling (apoptosis), and increased contractile recovery when compared with non-treated IR hearts or IR hearts pretreated with the inactive analog, KN-92. Blocking SR Ca(2+) loading and release (thapsigargin/dantrolene), mitochondrial Ca(2+) uniporter (ruthenium red/RU360), or mitochondrial permeability transition pore (cyclosporine A), significantly decreased infarct size, LDH release and apoptosis. SR-AIP hearts failed to show an increase in the phosphorylation of Thr(17) of phospholamban at the onset of reflow and exhibited a significant decrease in infarct size, apoptosis and necrosis respect to controls. The results reveal an apoptotic-necrotic pathway mediated by CaMKII-dependent phosphorylations at the SR, which involves the reverse NCX mode and the mitochondria as trigger and end effectors, respectively, of the cascade.
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PMID:The signalling pathway of CaMKII-mediated apoptosis and necrosis in the ischemia/reperfusion injury. 2006 4

Retinal pigment epithelial (RPE) cell integrity is critical for the survival of photoreceptor cells. Bcl-x(L) is a major anti-apoptotic Bcl-2 protein required for RPE cell survival, and phosphorylation of Bcl-x(L) at residue Ser-62 renders this protein pro-apoptotic. In this study, we identify serine/threonine protein phosphatase 2A (PP2A) as a key regulator of Bcl-x(L) phosphorylation at residue Ser-62 in ARPE-19 cells, a spontaneously arising RPE cell line in which Bcl-x(L) is highly expressed. We found that either PP2A inhibitor okadaic acid or depletion of catalytic subunit alpha of PP2A (PP2A/Calpha) by small interfering RNA enhanced Bcl-x(L) phosphorylation when activated with hydrogen peroxide and tumor necrosis factor alpha-induced oxidative stress. Disruption of PP2A/Calpha exacerbated oxidative stress-induced apoptosis. PP2A/Calpha colocalized and interacted with S62Bcl-x(L) in cells stressed with H(2)O(2)/tumor necrosis factor alpha. By contrast, the omega-3 fatty acid docosahexaenoic acid derivative, neuroprotectin D1 (NPD1), a potent activator of survival signaling, down-regulated oxidative stress-induced phosphorylation of Bcl-x(L) by increasing protein phosphatase activity. NPD1 also attenuated the oxidative stress-induced apoptosis by knockdown of PP2A/Calpha and increased the association of PP2A/Calpha with S62Bcl-x(L) as well as total Bcl-x(L). NPD1 also enhanced the heterodimerization of Bcl-x(L) with its counterpart, pro-apoptotic protein Bax. Thus, NPD1 modulates the activation of this Bcl-2 family protein by dephosphorylating in a PP2A-dependent manner, suggesting a coordinated, NPD1-mediated regulation of cell survival in response to oxidative stress.
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PMID:Neuroprotectin D1 induces dephosphorylation of Bcl-xL in a PP2A-dependent manner during oxidative stress and promotes retinal pigment epithelial cell survival. 2036 34

Forkhead box transcription factor, class 0 (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamiies of forkhead transcription factors such as FOXO1 (FKHR). FOXO3 (FKHRL1), FOXO4 (AFX) and FOXO6. All these FOXO members are expressed in the brain with different spatial patterns. FOXO1 is phosphorylated on three sites (Thr-24, Ser-256 and Ser-319) in phosphatidylinositol 3-kinase (PI3-K)/Akt-dependenr manner, thereby inhibiting apoptosis signals. We here documented dephosphorylation of FOXO1, FOXO3 and FOXO4 following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in the gerbil and mouse brains. The dephosphorylarion of FOXO1 following brain ischemia is in part mediated by constirutively active calcineurin in the mouse hippocampus. The activation of FOXOs preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FOXOl activation is accompanied by an increase in DNA binding activity for FOXO1-responsive element on the Fas ligand promoter. Thus, downstream targets induced by FOXOl include Fas ligand and Bcl-2-interacting mediator of cell death (Bim) in the brain ischemia. Accumulating evidence documented how FOXO activation is involved in the mechanisms of ischemic cell death. In this chapter, we document the activation mechanism of FOXO factors following brain ischemia and deline their downstream targets underlying neuronal death. The pathophysiological relevance of crosstalk between FOXOs and calcineurmn pathways is also discussed. Finally, we propose therapeutic perspectives to rescue neurons from delayed neuronal death by promoting the Akt signaling. Vanadium compounds, protein tyrosine phosphatase inhibitor, up-regulates Akt activity in the brain and thereby rescues neurons from delayed neuronal death by inhibiting FOXO-dependent and -independent death signals in neurons.
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PMID:Pathophysiological relevance of forkhead transcription factors in brain ischemia. 2042 21

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested whether cardiac-specific overexpression of a constitutively active (T35D, AA 1-65) inhibitor-1 (I-1c), could also affect cardiac apoptosis and heart failure progression induced by prolonged beta-adrenergic stimulation. We found that either acute or chronic expression of I-1c reduced isoproterenol (ISO)-induced apoptosis assessed by nuclear condensation, TUNEL staining and DNA fragmentation. The beneficial effects of I-1c were associated with increased expression of the anti-apoptotic protein Bcl-2, decreased expression of the pro-apoptotic protein Bax and reduced levels of active caspases as well as increased activation of ERK. These findings suggest that mitochondrial signaling and ERK activation may be involved in the I-1c cardioprotective effects against apoptosis induced by prolonged beta-adrenergic stimulation.
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PMID:Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis. 2052 8

Gossypol is an attractive therapeutic anti-tumor agent as an apoptosis inducer and is being evaluated in preclinical tests. However, the molecular mechanisms underlying apoptosis induction by gossypol in malignant cells have not been completely enunciated. Here we investigate the alterations of Bcl-2/Bcl-xL/Mcl-1 protein levels and Bcl-2 phosphorylation in gossypol-induced apoptosis in human leukemia HL-60 cells. We found that gossypol treatment inhibited cell growth and induced apoptosis in HL-60 cells. Bcl-2/Bcl-xL/Mcl-1 protein levels were slightly reduced and phosphorylation of Bcl-2 at threonine 56 (phospho T56) was not altered. However, phosphorylation of Bcl-2 at serine 70 (phospho S70) was strikingly down-regulated in gossypol-exposed cells. This reduction was found to be not only in both dose- and time-dependent fashion but also obviated by phorbol l2,13-dibutyrate (PDBu), an activator of protein kinase C (PKC). In addition, pre-treatment of PDBu partially prevented gossypol-induced apoptosis in HL-60 cells. Collectively, gossypol treatment can reduce phosphorylation of Bcl-2 at serine 70 in leukemia HL-60 cells and gossypol may be a promising therapeutical candidate for leukemia patients especially expressing phosphorylated Bcl-2 at Ser70.
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PMID:Gossypol inhibits phosphorylation of Bcl-2 in human leukemia HL-60 cells. 2063 48

Growth factor withdrawal from hemopoietic cells results in activation of the mitochondrial pathway of apoptosis. Members of the Bcl-2 family regulate this pathway, with anti-apoptotic members counteracting the effects of pro-apoptotic members. We investigated the effect on Mcl-1 function of mutation at a conserved threonine 163 residue (T163) in its proline, glutamate, serine, and threonine rich (PEST) region. Under normal growth conditions, Mcl-1 half-life increased with alteration of T163 to glutamic acid, but decreased with mutation to alanine. However, both T163 mutants exhibited greater pro-survival effects compared with the wild type, which can be explained by an increased stability of the T163A mutant in cytokine-starved conditions. Both the mutant forms exhibited prolonged binding to pro-apoptotic Bim in cytokine-deprived cells. The extent to which Mcl-1 mutants were able to exert their anti-apoptotic effects correlated with their ability to associate with Bim. We further observed that primary bone marrow derived macrophages survived following cytokine withdrawal as long as Bim and Mcl-1 remained associated. In our study, we were unable to detect a role for GSK-3-mediated regulation of Mcl-1 expression. Based on these results we propose that upon cytokine withdrawal, survival of hemopoietic cells depends on association between Mcl-1 and Bim. Furthermore, alteration of T163 of Mcl-1 may change the protein such that its association with Bim is affected, resulting in prolonged association and increased survival.
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PMID:Prevention of cytokine withdrawal-induced apoptosis by Mcl-1 requires interaction between Mcl-1 and Bim. 2092 92


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