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)

BAG-1 is a multifunctional and anti-apoptotic or anti-cell death protein that interacts with a variety of cellular proteins and affects their functions. On the cell surface, it binds to the cytosolic domain of the growth factor receptors and enhances the protection from cell death triggered by growth factor receptors. In the cytosol, it binds to Bcl-2 and heat shock protein, and modulates their functions. In the nucleus, it binds to a variety of nuclear hormone receptors and inhibits hormone-induced apoptosis. BAG-1 is widely overexpressed in a variety of tumour cell lines and cancer tissues. In addition, differential expression of BAG-1 isoforms has been observed. Preclinical studies indicate that overexpression of BAG-1, especially its nuclear and cytoplasmic isoforms, may be useful as a prognostic and/or predictive biomarker. Pilot clinical studies have demonstrated that overexpression of nuclear BAG-1 may be associated with a shorter survival in breast and laryngeal carcinomas. Conversely, overexpression of cytoplasmic BAG-1 may be associated with a better clinical outcome in early stage breast cancer and in non-small cell lung cancer. Further large-scale clinical studies are warranted to establish the role of BAG-1 as a novel prognostic and/or predictive biomarker in the clinical management of these common malignancies.
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PMID:BAG-1, an anti-apoptotic tumour marker. 1204 1

BAG-1 protein can be expressed as four isoforms of 50, 46, 33 and 29 kDa with different subcellular localizations, which may have different functions in anti-apoptosis, but the exact mechanism remains unclear. We constructed BAG-1 full length and deletion mutated plasmids in a pCR3.1 vector and established stable transfections of BAG-1 isoforms in low BAG-1 expressing C33A cells. Treatment of the transfected cells with cisplatin, staurosporine, paclitaxel and doxorubicine showed that BAG-1 p50, p46 and p33 isoforms enhanced the resistance to apoptosis. BAG-1 p50, p46 and p33 exhibited different degrees of apoptosis inhibition in the transfected cells and BAG-1 p46 isoform had the most pronounced effect on anti-apoptosis. BAG-1 p29 failed to protect the transfected cells from apoptosis. Resistance to apoptosis by BAG-1 isoforms was correlated with decreased caspase-3 activation. We also detected the expression of Bax, Bak, p53, Bcl-2, Bcl-X(L), AIF and MRP1 by Western blots. Bcl-2 protein expression was significantly increased in p50, p46 and p33 transfected cells, while the expression of Bax, Bak, p53, Bcl-X(L) and MRP1 was essentially unchanged. These in vitro results suggest that distinct isoforms of BAG-1 have different anti-apoptotic functions and their functions may be correlated to increased Bcl-2 expression.
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PMID:Distinct BAG-1 isoforms have different anti-apoptotic functions in BAG-1-transfected C33A human cervical carcinoma cell line. 1237 Aug 27

BAG-1 is a recently identified Bcl-2-interacting anti-apoptotic protein. The aim of our study was to investigate the immunohistochemical staining pattern of BAG-1 protein in patients with colorectal cancer and examine associations of BAG-1 expression with various clinicopathological factors and patient survival. Tumour samples were collected from 86 patients diagnosed with colorectal cancer. There was significant variation in the immunohistochemical staining patterns for BAG-1, including absent staining and staining of either the cytoplasm, nucleus or both. Twenty-one colorectal carcinomas (24.4%) exhibited a nuclear staining pattern whilst 56 (65.1%) exhibited cytoplasmic staining. The percentage of cases exhibiting nuclear BAG-1 positivity was significantly higher in distant metastasis-positive cases (55.6%) than in distant metastasis-negative cases (20.8%; P=0.036). Overall survival was significantly shorter for patients with tumours exhibiting BAG-1 positive nuclei than those with absent nuclear BAG-1-staining (P=0.011). In addition, the multivariate cox proportional hazard models indicated that nuclear BAG-1 expression was the only independent prognostic variable for mortality (P=0.013). These studies demonstrate that nuclear BAG-1 expression is a useful predictive factor for distant metastasis and a poor prognosis in patients with colorectal cancer.
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PMID:Nuclear BAG-1 expression reflects malignant potential in colorectal carcinomas. 1240 53

Bcl-2-associated athanogene (BAG)-family proteins are BAG domain-containing proteins that interact with the heat shock proteins 70, both constitutive Hsc70 and inducible Hsp70. BAG-family proteins bind through the BAG domain to the ATPase domain of Hsc70/Hsp70. The BAG domain, approximately 110 amino acids in length, is a conserved region at the carboxyl terminus and consists of three anti-parallel alpha helices based on X-ray crystallography and NMR studies. The second and third alpha-helices of the BAG domain interact with the ATP-binding pocket of Hsc70/Hsp70. Currently, six human BAG proteins have been reported, four of which have been shown to functionally bind Hsc70/Hsp70. BAG-family proteins regulate chaperone protein activities through their interaction with Hsc70/Hsp70. Over-expression of BAG-family proteins is found in several cancers and has been demonstrated in the laboratory to enhance cell survival and proliferation. The anti-apoptotic activities of BAG-family proteins may be dependent on their interactions with Hsc70/Hsp70 and/or binding to Bcl-2. Both BAG-1 and BAG-3/CAIR-1 interact with Bcl-2 and have been shown to have a supra-additive anti-apoptotic effect with Bcl-2. Several N-terminal domains or motifs have been identified in BAG-family proteins as well. These domains enable BAG-family proteins to partner with other proteins and potentially alter the activity of those target proteins by recruiting Hsc70/Hsp70. BAG-family proteins participate in a wide variety of cellular processes including cell survival (stress response), proliferation, migration and apoptosis.
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PMID:What's in the 'BAG'?--A functional domain analysis of the BAG-family proteins. 1240 44

The stress response in injured brain is well characterized after experimental ischemic and traumatic brain injury (TBI); however, the induction and regulation of the stress response in humans after TBI remains largely undefined. Accordingly, we examined injured brain tissue from adult patients (n = 8) that underwent emergent surgical decompression after TBI, for alterations in the inducible 72-kDa heat shock protein (Hsp70), the constitutive 73-kDa heat shock protein (Hsc70), and isoforms of the chaperone cofactor BAG-1. Control samples (n = 6) were obtained postmortem from patients dying of causes unrelated to CNS trauma. Western blot analysis showed that Hsp70, but not Hsc70, was increased in patients after TBI versus controls. Both Hsp70 and Hsc70 coimmunoprecipitated with the cofactor BAG-1. The 33 and 46, but not the 50-kDa BAG-1 isoforms were increased in patients after TBI versus controls. The ratio of the 46/33-kDa isoforms was increased in TBI versus controls, suggesting negative modulation of Hsp70/Hsc70 protein refolding activity in injured brain. These data implicate induction of the stress response and its modulation by the chaperone cofactor and Bcl-2 family member BAG-1, after TBI in humans.
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PMID:Alterations in inducible 72-kDa heat shock protein and the chaperone cofactor BAG-1 in human brain after head injury. 1255 71

BAG-1 was originally identified as a binding partner of anti-apoptotic factor Bcl-2 [Takayama et al., Cell 80 (1995) 279-284]. Exogenous expression of BAG-1 was reported to confer cells resistance to several stresses [Chen et al., Oncogene 21 (2002) 7050]. We have obtained human cervical cancer HeLa cells with down-regulated BAG-1 levels by using a highly specific and efficient RNA interference approach. Surprisingly, cells with down-regulated BAG-1 exhibited significantly lower sensitivity against several anti-cancer drugs than parental cells expressing normal levels of the protein. Furthermore, growth rate of the cells was reduced when BAG-1 was down-regulated. Activity of ERK pathway appeared to be decreased in BAG-1 down-regulated cells, as shown by the reduced phosphorylation of ERK1/2 proteins. Taken together resistance against anti-cancer drugs acquired by BAG-1 down-regulated cells may well be accounted for by the retardation of cell cycle progression, implicating the importance of BAG-1 in cell growth regulation.
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PMID:Down-regulation of Bcl-2-interacting protein BAG-1 confers resistance to anti-cancer drugs. 1256 51

Apoptosis has received widespread attention for its essential roles in biology, medicine and cancer. We previously found that normal, human papillomavirus (HPV) 16-immortalized and their transformed endocervical cells were increasingly resistant to apoptosis induced by a cancer therapeutic drug. Here, analogously, another common anticancer drug, 5-fluorouracil, in an ectocervical cell carcinogenesis model induced apoptosis in primary human ectocervical cells (HEC), whereas HPV18-immortalized HEC (HEC-18) and transformed HEC-18 (HEC-18T) were more resistant. Growth in serum/low density lipoprotein (LDL)-containing medium reversed resistance to 5-fluorouracil-induced apoptosis, particularly in HEC-18T. Cell viability results confirmed these findings. Using Western blots to compare protein levels with those of HEC not treated with 5-fluorouracil, the fold changes in HEC-18 and HEC-18T in LDL-free medium were 1.6-6.1-fold lower for pro-apoptotic p53, Bak and Bax. Four anti-apoptotic proteins were altered -2.1 to+14.6-fold for Bcl-2 and BAG-1 isoform p33 and p29. For BAG-1 p50 and p46, HEC-18 were weakly expressed and HEC-18T were moderately higher. Grown in LDL-containing medium, the differences in pro-apoptotic protein levels were mostly reversed. Expression was 1.4-32-fold higher in HEC-18 and HEC-18T of p53, Bax, BAG-1 p29, BAG-1 p33 and total BAG-1. These results showed that HEC carcinogenesis results in resistance to 5-fluorouracil-induced apoptosis, associated with reduced expression during carcinogenesis of pro-apoptotic proteins and increased expression of specific anti-apoptotic proteins.
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PMID:Apoptosis, 5-fluorouracil sensitivity and expression of apoptotic proteins in a human ectocervical cell carcinogenesis model using different media. 1270 50

BAG-1 has been identified as a Bcl-2-binding protein that inhibits apoptosis, either alone or in co-operation with Bcl-2. Here we show that BAG-1 inhibits p53- induced apoptosis in the human tumour cell line Saos-2. In contrast, BAG-1 was unable to inhibit the p53-independent pathway induced by apoptin, an apoptosis-inducing protein derived from chicken anaemia virus. Whereas BAG-1 seemed to co-operate with Bcl-2 to repress p53-induced apoptosis, co-expression of these proteins had no inhibitory effect on apoptin-induced apoptosis. Moreover, Bcl-2, and to some extent also BAG-1, paradoxically enhanced the apoptotic activity of apoptin. These results demonstrate that p53 and apoptin induce apoptosis through independent pathways, which are differentially regulated by BAG-1 and Bcl-2.
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PMID:BAG-1 inhibits p53-induced but not apoptin-induced apoptosis. 1464 36

To study the mechanism of action of BAG-1 in drug-induced apoptosis, we constructed an antisense BAG-1 vector and established a stably transfected cell line from BAG-1-over-expressing HeLa cells. Reduced BAG-1 protein was confirmed by Western blot. Treatment of the antisense BAG-1-transfected cells with the anti-cancer drugs staurosporine, paclitaxel, all-trans retinoic acid (ATRA), and N-(4-hydroxyphenyl) retinamide (4-HPR) resulted in significantly enhanced apoptosis and reduced cell viability relative to vector-transfected cells. While the expression of p53 was increased, the level of Bcl-2 and Bax was decreased. Cells underexpressing BAG-1 had reduced cytosolic cytochrome c level. Treatment with staurosporine and paclitaxel resulted in increased cytochrome c release from mitochondria, whereas there was no change induced by treatment with ATRA and 4-HPR. Our experiments suggest that BAG-1 inhibits anti-cancer drug-induced apoptosis through apoptosis regulation pathways that may involve the mitochondrial Bcl-2/Bax ratio, p53, and differential anti-cancer drug-mediated cytochrome c release.
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PMID:Antisense BAG-1 sensitizes HeLa cells to apoptosis by multiple pathways. 1468 Aug 5

BAG-1 (Bcl-2-associated athanogene-1) proteins interact with the HSC70 and HSP70 heat shock proteins and have been proposed to promote cell survival by coordinating the function of these chaperones with the proteasome to facilitate protein degradation. Consistent with this proposal, previous analyses in cancer cells have demonstrated that BAG-1 requires protein domains important for HSC70/HSP70 and proteasome binding in order to interfere with the growth inhibition induced by heat shock (Townsend, P. A., Cutress, R. I., Sharp, A., Brimmell, M., and Packham, G. (2003) Cancer Res., 63, 4150-4157). Moreover, cellular stress triggered the relocalization of the cytoplasmic BAG-1S (approximately 36 kDa) isoform to the nucleus, and both BAG-1S and the constitutively nuclear localized BAG-1L (approximately 50 kDa) isoform suppressed heat shock-induced apoptosis to the same extent, suggesting a critical role in the nucleus. Because ischemia (I) and reperfusion (R) are important stress signals in acute and chronic heart disease, we have examined the expression and function of BAG-1 proteins in primary cardiac myocytes (CMs) and the Langendorff-perfused intact heart. The expression of both BAG-1 isoforms, BAG-1S and BAG-1L, was rapidly induced following ischemia in rat CM, and this was maintained during subsequent reperfusion. In control hearts, BAG-1S and BAG-1L were readily detectable in both the nucleus and the cytoplasm. However, BAG-1S did not relocate to the nucleus following simulated I/R. BAG-1 interacted with both RAF-1 and HSC70 in CMs and the whole heart, and binding to HSC70 was increased following I/R. Overexpression of the human BAG-1S and BAG-1 M isoforms significantly reduced CM apoptosis following simulated I/R. By contrast, BAG-1L or BAG-1S fused to a heterologous nuclear localization sequence failed to protect CM. Finally, overexpression of BAG-1 deletion and point mutants unable to bind HSC70/HSP70 failed to offer cardioprotection. Surprisingly, a deletion mutant lacking the N-terminal ubiquitin-like domain, which mediates interaction with the proteasome, still promoted cardioprotection. Therefore, BAG-1 has a novel cardioprotective role, mediated via association with HSC70/HSP70, which is critical upon cytoplasmic localization but independent of the BAG-1 ubiquitin-like domain. Our studies demonstrate that BAG-1 can influence cellular response to stress by multiple mechanisms, potentially influenced by the cell type and nature of the stress signal.
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PMID:BAG-1 proteins protect cardiac myocytes from simulated ischemia/reperfusion-induced apoptosis via an alternate mechanism of cell survival independent of the proteasome. 1497 28


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