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 is a proto-oncogene which is involved in prolonging cell survival by inhibiting programmed cell death. Bax and bcl-x are members of the bcl-2 family; when overexpressed, they can counteract the ability of bcl-2 to inhibit apoptosis. This suggests a model in which the ratios of bcl-2 to bax and bcl-x can be used to determine response to therapy and prognosis. The expression of bcl-2, bax and bcl-x was studied in 50 ovarian carcinomas. The percentage of positive area immunostained (PPA) in the nucleus and cytoplasm of each ovarian carcinoma was quantitated in 15 high power fields by image cytometry. The ratios were obtained by dividing the PPA of bcl-2 by the PPA of bax and bcl-x. 17 of 50 ovarian carcinomas (34%) stained positively for bcl-2, 39 for bax (78%) and 47 for bcl-x (94%). Although there is no significant statistical correlation between expression of bcl-2, bax or bcl-x and grade (P = 0.15; P = 0. 47; P = 0.56), stage (P = 0.71; P = 0.6; P = 0.42), and overall or disease-free survival (P = 0.26; P = 0.55; P = 0.16), increased bcl-2 expression was demonstrated in patients with shortened overall and disease-free survival. Also, increased expression of bax and bcl-x was associated with increased overall and disease-free survival. Bcl-2:bax and bcl-2:bcl-x ratios less than 1 are associated with survival advantage, although not statistically significant (P = 0.83; P = 0.93). Image cytometric measurement of bcl-2, bax, and bcl-x expression is feasible. There is a tendency for their expression to correlate with prognosis in ovarian carcinomas.
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PMID:Bcl-2: bax and bcl-2: Bcl-x ratios by image cytometric quantitation of immunohistochemical expression in ovarian carcinoma: correlation with prognosis. 1067 44

The transcription factors of the Rel/NF-kappaB family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-kappaB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-kappaB control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-kappaB raised the issue of whether NF-kappaB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-kappaB differentially regulates the expression of particular Bcl-2-related death inhibitors and that it directly activates the expression of Bcl-x(L). While Bcl-x(L) was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-kappaB factors also upregulated bcl-x gene expression and this effect was antagonized by an inhibitor of NF-kappaB activity. The expression of bcl-x suppressed apoptosis in the presence or absence of NF-kappaB activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-kappaB directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x(L) and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-kappaB activity.
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PMID:The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). 1073 71

We simultaneously assessed bcl-2, bax, bcl-x(L) and bcl-x(S) expression levels by Western blotting on 53 primary untreated cervical cancers and 15 normal samples. Bcl-2 showed a trend to be lower in neoplastic than in normal samples (P<0.01), while no significant difference was observed for bax and bcl-x(L). Bcl-x(S) was barely detectable in only a few samples. Interestingly, in cervical cancer, bcl-2 and bcl-x(L) were directly correlated (P<0. 01). A significant association of bcl-2 levels with age (P<0.021) and menopausal status (P<0.041) in cervical cancer patients as well as in control patients was observed. Bcl-2, bax and bcl-x(L) levels in responding and non-responding patients were not differently distributed. Bcl-2, bax and bcl-x(L) are likely to play a role in the natural history of cervical tumors, but their clinical significance in predicting response to treatment and clinical outcome needs long-term follow-up studies.
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PMID:Bcl-2, bax, bcl-x(L) and bcl-x(S) expression in neoplastic and normal cervical tissue. 1081 75

Apoptosis is an important cofactor in the pathogenesis of a plethora of malignancies. However, little is known about modulation of the expression of bcl gene family in melanocytic tumors. To determine the role of bcl-2, bcl-x and bax in melanocytic tumors we investigated the differential expression of these genes via RT-PCR in tissue samples from human benign nevi, primary melanomas and melanoma metastases in comparison with normal skin. Bcl-2 was strongly expressed in 14/16 metastases (87.5%), whereas only 7/13 primary melanomas (53%), 7/15 nevi (46%) and 7/16 normal tissue samples (43%) showed expression of bcl-2 (P < 0.05). There was a strong indication of a correlation between tumor thickness and bcl-2 expression in nodular malignant melanomas. Expression of bcl-x was found in 16/16 melanoma metastases (100%), 11/13 primary melanomas (84%), 12/15 nevi (80%) and 10/16 normal tissue samples (62%) (P < 0.05). Bcl-xL expression increased from primary melanoma to melanoma metastases, whereas bcl-xS showed a decreasing expression level during melanoma progression. No differences in bax expression were seen between melanoma metastases, primary melanoma, nevi and normal tissue. Immunohistochemical investigations of another 53 tissue samples showed similar results. Our results strongly indicate that bcl-2 and bcl-xL gene expression increases with progression of malignant melanoma. Bcl-2 and bcl-xL expression could reflect an increased malignant potential caused by an inhibition of apoptosis and growth advantage for metastatic melanoma cells.
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PMID:Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma. 1086 10

The Bcl-2 family of proteins are key regulators of apoptosis. Bcl-xL, is an anti-apoptotic protein with a high degree of homology to Bcl-2; however, the signals that regulate Bcl-xL and Bcl-2 appear to be different. Levels of Bcl-xL, but not Bcl-2, are increased in response to various survival signals. Furthermore, an inverse correlation between the levels of Bcl-2 and Bcl-xL has been reported for a number of cancers. Although the precise molecules that control Bcl-xL activity are unclear, the STAT, Rel/NF-kappaB, and Ets transcription factor families have recently been reported to directly regulate the bcl-x gene. Activated Ras, integrin, vitronectin, and hepatocyte growth factor signaling cascades have also been linked to changes in Bcl-xL expression. Bcl-xL can also be affected by post-translational mechanisms. Here we review recent advances in identifying the signaling pathways and factors involved in regulation of the bcl-x gene.
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PMID:Regulation of Bcl-xL: a little bit of this and a little bit of STAT. 1108 53

Adenoviral vectors expressing wild-type p53 (Ad-p53) induce apoptosis in different types of cancer cells. The therapeutic utility of Ad-p53 is now being evaluated in prostate-cancer patients. Bcl-2 is frequently expressed by prostate-cancer cells and has previously been shown to inhibit p53-mediated cell death following genotoxic stress. We studied the impact of bcl-2 on Ad-p53-induced cell death in human prostate-cancer cells. Human prostate-cancer cell lines LNCaP (p53 wt) and PC3 (p53 mut) were stably transfected with bcl-2. After p53 transduction, cell viability, apoptosis induction and modulation of specific apoptosis-regulatory proteins were assessed. LNCaP vector control and bcl-2-expressing cells underwent similar decreases in viability associated with apoptosis induction following Ad-p53 infection. Increased bcl-2 expression provided significant protection to PC3 cells transduced with Ad-p53. These findings are correlated with modulations in bax, bcl-2, bcl-x(L) and p21 protein levels. These data suggest that Ad-p53 may be useful in the treatment of some prostate cancers.
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PMID:Molecular determinants of cell death induction following adenovirus-mediated gene transfer of wild-type p53 in prostate cancer cells. 1114 39

Programmed cell death is critical for normal nervous system development and is regulated by Bcl-2 and Caspase family members. Targeted disruption of bcl-x(L), an antiapoptotic bcl-2 gene family member, causes massive death of immature neurons in the developing nervous system whereas disruption of caspase-9, a proapoptotic caspase gene family member, leads to decreased neuronal apoptosis and neurodevelopmental abnormalities. To determine whether Bcl-X(L) and Caspase-9 interact in an obligate pathway of neuronal apoptosis, bcl-x/caspase-9 double homozygous mutants were generated. The increased apoptosis of immature neurons observed in Bcl-X(L)-deficient embryos was completely prevented by concomitant Caspase-9 deficiency. In contrast, bcl-x(-/-)/caspase-9(-/-) embryonic mice exhibited an expanded ventricular zone and neuronal malformations identical to that observed in mice lacking only Caspase-9. These results indicate both epistatic and independent actions of Bcl-X(L) and Caspase-9 in neuronal programmed cell death. To examine Bcl-2 and Caspase family-dependent apoptotic pathways in telencephalic neurons, we compared the effects of cytosine arabinoside (AraC), a known neuronal apoptosis inducer, on wild-type, Bcl-X(L)-, Bax-, Caspase-9-, Caspase-3-, and p53-deficient telencephalic neurons in vitro. AraC caused extensive apoptosis of wild-type and Bcl-X(L)-deficient neurons. p53- and Bax-deficient neurons showed marked protection from AraC-induced death, whereas Caspase-9- and Caspase-3-deficient neurons showed minimal or no protection, respectively. These findings contrast with our previous investigation of AraC-induced apoptosis of telencephalic neural precursor cells in which death was completely blocked by p53 or Caspase-9 deficiency but not Bax deficiency. In total, these results indicate a transition from Caspase-9- to Bax- and Bcl-X(L)-mediated neuronal apoptosis.
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PMID:Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. 1115 Mar 33

Apoptosis plays important roles in mammary development from early embryonic formation of the mammary gland to the regression that follows cessation of cycling. The most dramatic occurrence of apoptosis is found during mammary involution. Most of the secretory epithelium in the lactating breast undergoes apoptosis as the mammary gland regresses and is reorganized for another cycle of lactation. We used the morphology, biochemical changes, and gene expression detected in apoptotic mammary epithelium during involution as a model for studying cell death during other stages of mammary development and for approaching the failure of apoptosis found in mammary hyperplasia. Morphological studies and gene expression have suggested that apoptosis during involution is comprised of two phases: an early limited apoptosis in response to hormone ablation and later protease promoted widespread apoptosis in response to altered cell-matrix interactions and loss of anchorage. We examined protein expression during involution for changes associated with loss of hormone stimulation and altered cell-matrix interactions. One of the proteins whose expression is able to inhibit apoptosis, and is altered during mammary epithelial cell was the serine-threonine protein kinase, Akt 1. Akt 1 activation is common to hormone, growth factor, and anchorage-mediated survival of epithelial cells. We found regulated expression of activated Akt 1 in the mammary gland during involution. Akt 1 activation peaked in pregnancy and lactation, and decreased significantly during apoptosis in mammary involution. Mechanisms of Akt 1 action include modulation of the ratio bcl-2 family members implicated in control of apoptosis. Bcl-2 family proteins were also expressed in pattern consistent with Akt 1 regulation. These observations led us to examine expression of activated Akt 1 and bcl-2 family proteins in premalignant hyperplasias. Akt 1 activation was increased; expression of anti-apoptotic proteins bcl-2 and bcl-x was strongly increased while pro-apoptotic bax was greatly diminished in three different lines of transplantable premalignant mammary hyperplasia. This data suggest that activation of Akt 1 by hormone- or anchorage-mediated pathways regulates survival of mammary epithelium and can contribute to initiation of neoplasia. These data suggest that perturbation of normal cell turnover can contribute to initiation of neoplasia.
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PMID:Apoptosis in normal and neoplastic mammary gland development. 1116 65

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-kappaB (NFkappaB). We investigated the effect of NGF on the expression of Bcl-xL, an anti-apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1-10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFkappaB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFkappaB p65 subunit. NGF-induced NFkappaB activity and Bcl-xL expression were inhibited in cells overexpressing the NFkappaB inhibitor, IkappaBalpha. Unlike tumor necrosis factor-alpha (TNF-alpha), however, NGF-induced NFkappaB activation occurred without significant degradation of IkappaBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein-tagged IkappaBalpha. Moreover, in contrast to TNF-alpha, NGF failed to phosphorylate IkappaBalpha at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IkappaBalpha potently suppressed NFG-, but not TNF-alpha-induced NFkappaB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-alpha-, but not NGF-induced NFkappaB activation. We conclude that NGF and TNF-alpha induce different signaling pathways in neurons to activate NFkappaB and bcl-x gene expression.
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PMID:Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. 1126 66

There is ample evidence that deregulation of apoptosis results in the development, progression, and/or maintenance of cancer. Since many apoptotic regulatory genes (e.g. bcl-x) code for alternatively spliced protein variants with opposing functions, the manipulation of alternative splicing presents a unique way of regulating the apoptotic response. Here we have targeted oligonucleotides antisense to the 5'-splice site of bcl-x(L), an anti-apoptotic gene that is overexpressed in various cancers, and shifted the splicing pattern of Bcl-x pre-mRNA from Bcl-x(L) to Bcl-x(S), a pro-apoptotic splice variant. This approach induced significant apoptosis in PC-3 prostate cancer cells. In contrast, the same oligonucleotide treatment elicited a much weaker apoptotic response in MCF-7 breast cancer cells. Moreover, although the shift in Bcl-x pre-mRNA splicing inhibited colony formation in both cell lines, this effect was much less pronounced in MCF-7 cells. These differences in responses to oligonucleotide treatment were analyzed in the context of expression of Bcl-x(L), Bcl-x(S), and Bcl-2 proteins. The results indicate that despite the presence of Bcl-x pre-mRNA in a number of cell types, the effects of modification of its splicing by antisense oligonucleotides vary depending on the expression profile of the treated cells.
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PMID:Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death. 1127 82


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