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 mechanisms by which apoptosis is prevented by survival factors are largely unknown. Using an interaction cloning approach, we identified a protein that binds to the intracellular domain of the hepatocyte growth factor (HGF) receptor. This protein was identified as BAG-1, a recently characterized Bcl-2 functional partner, which prolongs cell survival through unknown mechanisms. Overexpression of BAG-1 in liver progenitor cells enhances protection from apoptosis by HGF. Association of the receptor with BAG-1 occurs in intact cells, is mediated by the C-terminal region of BAG-1 and is independent from tyrosine phosphorylation of the receptor. Formation of the complex is increased rapidly following induction of apoptosis. BAG-1 also enhances platelet-derived growth factor (PDGF)-mediated protection from apoptosis and associates with the PDGF receptor. Microinjection or transient expression of BAG-1 deletion mutants shows that both the N- and the C-terminal domains are required for protection from apoptosis. The finding of a link between growth factor receptors and the anti-apoptotic machinery fills a gap in the understanding of the molecular events regulating programmed cell death.
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PMID:HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. 894 43

Resolution of glomerular inflammation requires the removal of proliferating resident glomerular mesangial cells, but excessive loss of glomerular cells is a feature of postinflammatory scarring. Because apoptosis regulates mesangial cell number in glomerular inflammation, we have studied the exogenous control of apoptosis triggered in cultured mesangial cells by stimuli likely to be important in vivo. Apoptosis could be induced by serum deprivation to model decreased availability of survival factors, by etoposide as an example of DNA-damaging agents, by ligation of mesangial cell Fas, and by protein synthesis inhibition by cycloheximide. Insulin-like growth factor I (IGF-I), IGF-II, and basic fibroblast growth factor were each able to suppress apoptosis induced by serum deprivation, whereas TGF-beta 1, epidermal growth factor, and platelet-derived growth factor had no effect. IGF-I and IGF-II (but not basic fibroblast growth factor) were also able to protect cells from apoptosis induced by etoposide or cycloheximide. However, Fas-mediated apoptosis was resistant to suppression by all three cytokines. None of the cytokines tested caused a change in the levels of expression of Bcl-2, Bax, Bcl-x, or Bak proteins. The survival-promoting properties of serum-free medium conditioned by mesangial cells was abrogated by neutralizing IGF-I Ab. These experiments are the first to define cytokines that inhibit apoptosis and thereby promote survival of mesangial cells, and the data indicate a paracrine survival signaling role for IGF-I. Finally, the data show that Fas ligation can override cytokine survival signaling, emphasizing a candidate role for this molecule in the undesirable apoptotic loss of mesangial cells during the progression of glomerular scarring.
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PMID:Cytokines promote glomerular mesangial cell survival in vitro by stimulus-dependent inhibition of apoptosis. 937 83

In human neuroblastoma SH-SY5Y cells, treatment with immunosuppressants such as FK506, cyclosporin A or rapamycin for 4 days induced the enhancement of the 27-kDa Bcl-2alpha protein level. Among immunosuppressants, rapamycin has most potency. Treatment with herbimycin A or wortmannin also enhanced Bcl-2 expression, but the BB type of platelet-derived growth factor decreased the level. These results suggest that Bcl-2 expression is probably regulated by the cascade of tyrosine kinase, phosphatidylinositol 3-kinase and rapamycin-sensitive p70 S6-kinase in human neuroblastoma SH-SY5Y cells.
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PMID:Possible involvement of rapamycin-sensitive pathway in Bcl-2 expression in human neuroblastoma SH-SY5Y cells. 941 36

In a chemically defined serum-free culture system, platelet-derived growth factor (PDGF) as the only externally applied growth factor, in concert with corticosterone, 3-isobutyl-1-methylxanthine (IBMX) and low insulin (1nM), stimulates adipose conversion of 3T3-L1 preadipocytes. Omission of PDGF during the induction period results in loss of differentiation competence and apoptotic cell death. Induction of apoptosis is shown to be clearly mediated by PDGF withdrawal, since neither corticosterone nor IBMX affect the apoptotic behaviour of 3T3-L1 cells. Cell viability in the absence of the survival factor PDGF could be achieved by application of high insulin (1 microM) or ectopical expression of the anti-apoptotic proto-oncogene Bcl-2. However, PDGF-independent suppression of cell death does not trigger adipose conversion in the presence of corticosterone and IBMX. Therefore, we conclude that suppression of apoptosis per se is not permissive for differentiation of 3T3-L1 preadipocytes and PDGF might exert some additional differentiation-promoting effect(s).
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PMID:The role of PDGF-dependent suppression of apoptosis in differentiating 3T3-L1 preadipocytes. 986 Jan 38

Bcl-2 may account in part for the maintenance of hypercellularity in human glomerular diseases through preventing cell death and by counteracting bax which may be expressed to regulate excessive proliferation. This process is associated with the effect of PDGF B-chain expression. Bax expression may be important in the cell loss leading to glomerulosclerosis and TGF-beta1 participates in this process by increasing bax expression. Thus, the balance of bcl-2/bax expression may be critical in the course of human glomerular diseases.
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PMID:Expression of bcl-2 and bax in glomerular disease. 1004 52

Mortal human fibroblasts can be partially transformed by the bovine papillomavirus E5 oncoprotein through activation of the platelet-derived growth factor beta receptor. Here, we report that these cells undergo massive apoptosis 2 weeks after confluence. Although activation of caspase 3 was observed in the apoptotic cells, it was not required for apoptosis. The appearance of the mitochondrial proteins cytochrome c and apoptosis-inducing factor in cytosolic and nuclear compartments, respectively, provided a basis for mitochondrial dysfunction and a caspase-independent mechanism of apoptosis in these cells. Although an activating conformational change in Bax also was evident in the apoptotic cells, enforced overexpression of Bcl-2 was insufficient to prevent apoptosis. Finally, a small peptide present in the conditioned medium from dying transformed cells appeared responsible for inducing apoptosis through affecting a conformational change in Bax and eventual relocalization of apoptosis-inducing factor to the nucleus. Thus, an atypical apoptotic pathway is activated in mortal human fibroblasts in response to transformation induced by sustained receptor tyrosine kinase activation.
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PMID:Apoptosis of mortal human fibroblasts transformed by the bovine papillomavirus E5 oncoprotein. 1249 59

H1-A, a pure compound used in traditional Chinese medicine, is effective in the treatment of autoimmune disorders of MRL lpr/lpr mice. We have previously reported that after 8 weeks of oral therapy with H1-A, 40 microg/kg/day, MRL lpr/lpr mice demonstrated significantly less proteinuria, lower serum creatinine levels, and less renal mesangial proliferation than mice in an untreated group. To clarify the pharmacologic properties of H1-A, we studied its cellular and subcellular effects in cultured human mesangial cells. Our results show that H1-A inhibits cell proliferation and promotes the apoptosis of interleukin (IL)-1- and platelet-derived growth factor (PDGF)-BB-activated human mesangial cells in vitro. Uptake of tritiated thymidine was nearly totally suppressed by the addition of 12.5 micromol/L H1-A (counts per minute decreased from 3905 +/- 70 to 141 +/- 5). The population of S-phase cells decreased from 15.5% +/- 1.7% to 10.0% +/- 0.3%, and G0 + G1 phase cells increased from 68.8% +/- 0.07% to 74.6% +/- 0.05%. This suppression was not a result of cytotoxicity. Apoptosis of human mesangial cells was detectable after treatment with 12.5 or 25 micromol/L H1-A. Using immunoprecipitation and immunoblotting, we found that H1-A inhibits tyrosine phosphorylation of human mesangial proteins and that Bcl-2 and Bcl-XL were probably among these proteins. These findings suggest that H1-A modulates some subcellular signal-transduction pathways and changes the balance between proliferation and apoptosis of mesangial cells in vitro or in vivo. H1-A may be effective in the management of autoimmune disorders, and the modulation of the signal transduction proteins Bcl-2 and Bcl-XL may represent a target for future pharmacologic interventions.
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PMID:H1-A extracted from Cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XL. 1251 71

The call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become more urgent. Inhibition of angiogenesis continues to be one of the main streams in the current cancer drug discovery activity. Insights into tumor angiogenesis biology have led to the identification of a number of molecules, which are important for the progression of these processes. Of particular interest is a group of growth factors including fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. These growth factors and their corresponding receptor tyrosine kinases have become important targets for inhibition of the proliferation of endothelial cells, the main component of blood vessels. The validated targets for inhibition of angiogenesis also include a family of matrix metalloproteinases and cell adhesion molecules. In the closely related area, protein kinases have emerged as one of the most important targets for drug discovery. Besides growth factor receptor tyrosine kinases, numerous other protein kinases implicated in malignancies have been identified including non-receptor kinases such as Bcl-Abl and Src kinases. In addition, the cell cycle regulators (cyclin-dependent kinases, p21 gene) and apoptosis modulators (Bcl-2 oncoprotein, p53 tumor suppressor gene, survivin protein, etc) have also attracted renewed interest as potential targets for anticancer drug discovery. Other molecular targets include protein farnesyltransferase (FTase), histone deacetylase (HDAC), and telomerase, which have essential roles in cellular signal transduction pathways (FTase, HDAC) and cell life-span (telomerase). This review presents a comprehensive summary and discussion on the most important targets currently attracting a great deal of interest in contemporary anticancer drug design and discovery. Recent advances complementing these targets are also highlighted.
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PMID:Current targets for anticancer drug discovery. 1255 68

Inhibiting tyrosine kinases has recently emerged as a therapeutic modality in several forms of neoplasia. The tyrosine kinase inhibitor STI571 (IMATINIB MESYLATE; GLEEVEC; GLIVEC) is a case in point as it has shown promise in the treatment of malignancies expressing the BCR/ABL fusion protein. In addition to BCR/ABL, STI571 inhibits the tyrosine kinase moieties of several cell surface receptors including the platelet-derived growth factor (PDGF) receptors and c-Kit. Previous work demonstrated that c-Kit activation supports migration, invasion and, survival of certain colorectal carcinoma cells including DLD-1. Here we describe that blocking c-Kit with STI571 inhibits these malignant traits not only in DLD-1 cells but also in two early passage colorectal carcinoma cell strains. Specifically, STI571 inhibited anchorage-independent colony formation and cell scattering in semi-solid medium. Furthermore, it enhanced apoptosis susceptibility and abrogated invasion of DLD-1 cells through Matrigel. In addition, STI571 treatment affected the balance of the Bcl-2 family of apoptosis regulators on favor of a pro-apoptotic phenotype. Specifically, STI571 treatment of DLD-1 cells was associated with lower levels of Bcl-2 expression accompanied by de novo expression of Bcl-xS. Finally, STI571 acted as a chemosensitizing agent in DLD-1 cells when used in combination with 5-fluorouracil.
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PMID:Inhibition of cell survival and invasive potential of colorectal carcinoma cells by the tyrosine kinase inhibitor STI571. 1500 35

In vitro studies suggest that cyclooxygenase-2 (COX-2) induces angiogenesis by stimulating angiogenic growth factors while inhibiting apoptosis in cancer cell lines. A series of 107 gastric adenocarcinoma cases that had undergone gastrectomy was studied to determine the correlation between COX-2 expression, angiogenesis, and apoptosis in human gastric cancer tissue. COX-2, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and Bcl-2 were stained by single and dual immunoassaying methods. Microvessel density was determined by immunostaining for CD34. Apoptosis was evaluated with the TUNEL assay. COX-2 expression was positive exclusively in cancer cells in 46 cases (43%). COX-2 expression significantly correlated with VEGF and PDGF expression. Dual staining for COX-2 and VEGF showed that colocalization of these proteins was most frequent at the advancing edge of cancer cells. Microvessel density was higher in COX-2-and VEGF-positive cases than in COX-2- and VEGF-negative cases. In addition, COX-2 expression correlated with Bcl-2 expression. The apoptotic index was lower in COX-2-positive cancer cells than in COX-2-negative cases. Multivariate analysis revealed that coexpression of COX-2 and VEGF, age, lymph node status, and serosal invasion were independent prognostic factors for overall survival in gastric cancer patients. Therefore, these data suggest that COX-2 contributes to gastric cancer development by promoting angiogenesis and inhibiting apoptosis.
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PMID:Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. 1511 31


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