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)

Bcl-2-family members (Bcl-2, Bax, Bcl-w and Bcl-x(L)) are crucial integrators of signals for cell survival and death; the pro- or antiapoptotic activities of these proteins are regulated by their subcellular localization. Bcl-2 directly inserts into the membranes, where it acts; however, Bax requires a stimulus-dependent translocation from an inactive cytosolic to an active membrane-inserted state. Recently, a novel mechanism is described for the survival factor Bcl-w, which is active while weakly associated with mitochondria. In apoptotic cells, a BH3-only protein neutralizes the survival activity of Bcl-w by binding to its "hydrophobic pockets", thereby releasing its C-terminal domain and allowing its insertion into the membrane. Here, we discuss the importance of this finding for a better understanding of the action mode of Bcl-w and other Bcl-2-family members.
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PMID:Bcl-w(edding) with mitochondria. 1472 75

Energy restriction (ER) inhibits mammary carcinogenesis and results in a marked reduction in tumor size, effects likely to be explained by ER-mediated induction of apoptosis. The goal of this study was to investigate the molecular mechanism(s) accounting for apoptosis induction. To do this, chemically induced mammary carcinomas were evaluated from rats that were ad libitum fed (control), 40% ER, or 40% ER but energy repleted for 7 days before study termination (ER-REP); the ER-REP group permitted the determination of the reversibility of ER-mediated effects. Cleaved products of poly(ADP-ribose) polymerase 1 were elevated by ER (P < 0.025) providing biochemical evidence of apoptosis induction. cDNA microarray analysis identified the Bcl-2, CARD, and IAP functional gene groupings as being involved in apoptosis induction. Consistent with the microarray data, the activities of caspases 9 and 3 were observed to be approximately 2-fold higher in carcinomas from ER rats (P < or =0.01), whereas caspase 8 activity was similar in carcinomas from all three of the groups. This evidence that ER-induced apoptosis mediated by the mitochondrial pathway was additionally supported by the finding that levels of Bcl-2, Bcl-xl, and XIAP protein were significantly lower (P < 0.01), and levels of Bax and Apaf-1 were elevated (P < 0.02) in ER carcinomas versus those carcinomas from control or ER-REP rats. Additional studies revealed that Akt phosphorylation (activation) was reduced in mammary carcinomas from ER rats. Thus, it appears that ER induces apoptosis in mammary carcinomas via a cell survival factor-dependent pathway.
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PMID:Identification of the apoptosis activation cascade induced in mammary carcinomas by energy restriction. 1497 70

Although apoptosis has been considered the typical mechanism for physiological cell death, presently alternative mechanisms need to be considered. We previously showed that fibroblast growth factor-2 (FGF2) could act as a survival factor for neural precursor cells. To study the death mechanism activated by the absence of this growth factor, we followed the changes in cell morphology and determined cell viability by staining with several dyes after FGF2 removal from mesencephalic neural-progenitor-cell cultures. The changes observed did not correspond to those associated with apoptosis. After 48 h in the absence of FGF2, cells began to develop vacuoles in their cytoplasm, a phenotype that became very obvious 3-5 days later. Double-membrane vacuoles containing cell debris were observed. Vacuolated cells did not stain with either ethidium bromide or trypan Blue, and did not show chromatin condensations. Nonetheless, during the course of culture, vacuolated cells formed aggregates with highly condensed chromatin and detached from the plate. Neural progenitor cells grown in the presence of FGF2 did not display any of those characteristics. The vacuolated phenotype could be reversed by the addition of FGF2. Typical autophagy inhibitors such as 3-MA and LY294002 inhibited vacuole development, whereas a broad-spectrum caspase inhibitor did not. Interestingly, Bcl-2 overexpression retarded vacuole development. In conclusion, we identified a death autophagy-like mechanism activated by the lack of a specific survival factor that can be inhibited by Bcl2. We propose that anti-apoptotic Bcl2 family members are key molecules controlling death activation independently of the cell degeneration mechanism used.
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PMID:Growth factor deprivation induces an alternative non-apoptotic death mechanism that is inhibited by Bcl2 in cells derived from neural precursor cells. 1497 82

The central role of T cell activation in hepatocellular injury has been well documented. In this article, we provide evidence suggesting that T cells may also play a protective role in liver disease by releasing interleukin-22 (IL-22), a recently identified T cell-derived cytokine whose biological significance is unclear. IL-22 messenger RNA and protein expression are significantly elevated in T cell-mediated hepatitis induced by concanavalin A (ConA) but are less extensively elevated in the carbon tetrachloride-induced liver injury model. Activated CD3(+) T cells are likely responsible for the production of IL-22 in the liver after injection of ConA. The IL-22 receptor is normally expressed at high levels by hepatocytes and further induced after ConA injection. IL-22 blockade with a neutralizing antibody reduces signal transducer and activator of transcription factor 3 (STAT3) activation and worsens liver injury in T cell-mediated hepatitis, whereas injection of recombinant IL-22 attenuates such injury. In vitro treatment with recombinant IL-22 or overexpression of IL-22 promotes cell growth and survival in human hepatocellular carcinoma HepG2 cells. Stable overexpression of IL-22 in HepG2 cells constitutively activates STAT3 and induces expression of a variety of antiapoptotic (e.g., Bcl-2, Bcl-xL, Mcl-1) and mitogenic (e.g., c-myc, cyclin D1, Rb2, CDK4) proteins. Blocking STAT3 activation abolishes the antiapoptotic and mitogenic actions of IL-22 in hepatic cells. In conclusion, the T cell-derived cytokine IL-22 is a survival factor for hepatocytes; this suggests that T cell activation may also prevent and repair liver injury by releasing hepatoprotective cytokine IL-22 in addition to its previously documented central role in hepatocellular injury.
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PMID:Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. 1512 62

We have previously reported that expression of the constitutively active mutant of Galpha11 or stimulation of m1 muscarinic acetylcholine receptor induced proteolytic activation of Rho-associated kinase (ROCK-I) by caspase and apoptosis in HeLa cells. In this study, we investigate the molecular mechanisms of Galphaq/11-induced apoptosis in m1 muscarinic acetylcholine receptor-expressing HeLa cells. Overexpression of Bcl-2 inhibited carbachol-induced ROCK-I cleavage, indicating a mitochondrial apoptotic pathway. Overexpression of the constitutively active mutant of Akt that delivers an anti-apoptotic survival signal had a similar influence. Insulin, a major survival factor in many cells, strongly increased phosphorylation of Akt, which was completely blocked by carbachol. This latter effect was partially inhibited by treatment with the tyrosine phosphatase inhibitors, orthovanadate and pervanadate. In parallel with these observations, carbachol attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1, an effect eliminated by orthovanadate. On the other hand, carbachol induced rapid stimulation of endogenous RhoA, and expression of a constitutively active mutant of RhoA increased ROCK-I cleavage. Orthovanadate and the dominant negative mutant of RhoA partially, and their combination completely, inhibited carbachol-induced ROCK-I cleavage and apoptosis. These results demonstrate that Gq/11 signaling induces apoptosis by reducing insulin-stimulated Akt phosphorylation through tyrosine dephosphorylation and activating RhoA in HeLa cells.
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PMID:Galphaq/11 signaling induces apoptosis through two pathways involving reduction of Akt phosphorylation and activation of RhoA in HeLa cells. 1524 75

The primary abnormality in chronic lymphocytic leukemia (CLL) is a defect in apoptosis, probably related to alterations in the expressions of Bcl-2 family members. In transgenic mice over expressing the anti-apoptotic Bcl-2 family member, myeloid cell factor-1 (Mcl-1), B cell lymphomas occur. Moreover, mice conditional for the loss of Mcl-1 display a profound reduction in B and T lymphocytes. This suggests that Mcl-1 is an essential survival factor in lymphocytes. In the present study, we have evaluated the role of Mcl-1 in CLL. Mcl-1 protein expression was measured by Western blot analysis in the CLL cells of 45 patients and correlated with clinical variables and survival. Mcl-1 levels were similar in 29 patients to normal B and T lymphocytes, were decreased in 8 patients and increased in 12 patients. An inverse correlation was found between Mcl-1 expression and Rai stage (P = 0.001). When assessed by flow cytometry, Mcl-1 expressions were normally distributed among CLL cells in individual patients and the mean levels correlated with those obtained by Western blotting. To evaluate the role of Mcl-1 in drug resistance, Mcl-1 levels were sequentially measured in the leukemic cells of 4 CLL patients during therapy with fludarabine (Flu). The Mcl-1 levels were found to increase in 2 patients while the peripheral blood lymphocyte counts dropped, suggesting that the residual drug-resistant cells had the highest Mcl-1 levels. Primary CLL cells were also treated with chlorambucil (CLB) or Flu in vitro and the Mcl-1 levels decreased correlating with the sensitivity of these cells to undergo apoptosis. Drug sensitivities of the CLL cells to CLB and Flu were also measured by MTT assay and the concentrations of drug required to decrease cell viability by 50% (IC50) varied from 1.9 to 9.27 microM for Flu (median, 9.4 microM) and 10 to 32.5 microM (median, 5.5 microM) for CLB. The sensitivities of the leukemic cells to CLB correlated inversely with Mcl-1 levels (P < 0.05). These results suggest that Mcl-1 may contribute to cell survival in CLL.
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PMID:Role of myeloid cell factor-1 (Mcl-1) in chronic lymphocytic leukemia. 1537 Feb 46

Insulin-like growth factor-I (IGF-I) plays an important role as a survival factor during mammary gland development and remodelling during involution of the mature/lactating mammary gland, and elevated concentrations have been associated with increased risk of breast cancer. The actions of IGF-I are modulated by a family of binding proteins (IGFBPs) and we have shown that IGFBP-5 is associated with cell death in the mammary gland and more recently provided the first evidence that it is causally related to apoptosis of the mammary gland. A transgenic mouse expressing IGFBP-5 on a mammary-specific promoter led to impaired mammary development involving inhibition of IGF-signalling and involving members of the Bcl-2 family. Subsequent studies in vitro and in vivo using exogenous IGFBP-5 treatment have added support to this concept. Although the effects of IGFBP-5 did appear to involve inhibition of IGF action, a role for IGF-independent effects cannot be ruled out. Such IGF-independent effects involve potential interactions with components of the extracellular matrix involved in tissue remodelling including plasminogen activator inhibitor-1 (PAI-1). In addition, intracellular events involving nuclear localisation of IGFBP-5 have been shown to have the ability to inhibit cell proliferation. Thus, IGFBP-5 seems important for regulating both apoptosis and cell proliferation in the mammary gland during development and post-lactation involution.
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PMID:The role of IGFBP-5 in mammary gland development and involution. 1545 Oct 73

Multiple myeloma is a fatal B cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL-6 is a major survival factor for myeloma cells. Bcl-2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro-apoptotic proteins that have only a single Bcl-2 homology domain, BH3-only, are potent inducers of apoptosis. In myeloma cells, Mcl-1 has been shown to be a major anti-apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3-only protein Bim and its interaction with Mcl-1. The three major Bim isoforms are expressed in myeloma cells and are negatively regulated by IL-6. Blockade of IL-6 signaling induces an up-regulation of Bim concomitant to Mcl-1 down-regulation. Of major interest, Bim is found strongly associated with Mcl-1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Bim is also found strongly associated to Bcl-2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl-1 neutralizes Bim through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro-apoptotic function and to activate Bax.
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PMID:The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. 1545

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1beta-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2alpha or kinase-inactive CK2alpha (K68M) or CK2alpha' (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2alpha expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.
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PMID:Influence of casein kinase II in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human rhabdomyosarcoma cells. 1603 52

In replicative senescence, cells undergo permanent exit from cell cycle traverse; this is traditionally thought to occur at the end of a culture's in vitro life span, after serial passaging. In general, the checkpoint for replicative senescence is found at the G(1)/S border, controlled by the modulation of a battery of proteins, typified by gaining inhibitors of cell cycle traverse, such as cyclin-dependent kinases or RB hyperphosphorylation, and losing pro-proliferation gene expressions such as c-fos, c-myc, and a cadre of proliferation-dependent kinases. Here, we present evidence that replicatively senescent fibroblasts are resistant to apoptotic death, associated with a lack of key enzyme activities, caspase-3 being the chief executioner. This observation, coupled with our earlier report that senescent fibroblasts maintain persistently high levels of pro-survival factor Bcl-2, suggests that the molecular signaling program present in fibroblasts at the end of their in vitro life span may not only cater to the state of permanent exit from cell cycle traverse, but also dictate an inability to commit cellular suicide. Future experiments will reveal whether replicatively senescent fibroblasts that can neither proliferate nor die contribute to organismic aging, and whether their accumulation over time in tissue becomes detrimental to the normal aging process.
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PMID:Senescent fibroblasts resist apoptosis by downregulating caspase-3. 1554 72


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