Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins encoded by bcl-2 family genes are important regulators of programmed cell death and apoptosis. Alterations in the expression of these apoptosis-regulating genes can contribute to the origins of cancer, as well as adversely influence tumor responses to chemo- and radiotherapy. Using antibodies specific for the Bcl-2, Bax, Bcl-X, and Mcl-1 proteins in combination with immunohistochemical methods, we examined for the first time the expression of these bcl-2 family genes in 64 cases of adenocarcinoma of the prostate, including 10 Gleason grade 2 to 4 tumors, 21 grade 5 to 7 tumors, 17 grade 8 to 10 tumors, 8 lymph node metastases, and 8 bone metastases. In addition, 24 cases of prostatic intraepithelial neoplasia (PIN) or PIN coexisting with carcinoma were also evaluated. All immunostaining results were scored with regard to approximate percentage of positive tumor cells and relative immunostaining intensity. Expression of the anti-apoptotic protein Bcl-2 was present in 16 of 64 (25%) adenocarcinomas and tended to be more frequent in high grade tumors (Gleason grade 8 to 10; 41%) and nodal metastases (38%) than in lower grade (Gleason 2 to 7) primary tumors (16%; P < 0.05). Bcl-X was expressed in all 64 (100%) tumors evaluated. Bcl-X immunointensity was generally stronger in high grade primary tumors (grade 8 to 10) and metastases compared with PIN and low grade neoplasms (P < 0.0001). In addition, the proportion of specimens with > 50% Bcl-X-immunopositive tumor cells also was higher in advanced grade primary tumors (Gleason 8 to 10) and metastases than in PIN and low grade tumors (Gleason 2 to 7; P < 0.005). The anti-apoptotic protein Mcl-1 was expressed in 52 of 64 (81%) tumors, compared with only 9 of 24 (38%) cases of PIN (P < 0.001). In addition, the percentage of Mcl-1-positive cells was typically higher in Gleason grade 8 to 10 tumors and metastases than in PIN or lower grade tumors (P = 0.025). In contrast, the pro-apoptotic protein Bax was expressed in all prostate cancers evaluated, with high percentages of immunopositive cells and strong immunointensity typically occurring regardless of tumor grade. The findings suggest that expression of several anti-apoptotic members of the bcl-2 gene family, including bcl-2, bcl-X, and mcl-1 increases during progression of prostate cancers, a finding that may be relevant to the hormone-insensitive, metastatic phenotype of most advanced adenocarcinomas of the prostate.
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PMID:Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. 862 25

Whereas in normal human thyroid tissue total cell mass is maintained by a balance between cell proliferation and apoptosis, the programmed cell death, in thyroid tumors this equilibrium is disrupted. In tumor cells, an augmented proliferation rate is no longer counterbalanced by an equally enhanced apoptosis resulting in an increased netto growth rate. To investigate regulation of apoptosis in thyroid tumors, we analyzed the expression of apoptosis-related proteins of the bcl-2 family in human thyroid tissues and in the human thyroid carcinoma cell lines FTC 133, HTC, HTC-TSHr and HTh74. In comparison to normal tissue, we detected an increased expression of the anti-apoptotic protein bcl-2 in adenomas, whereas follicular carcinomas showed various expression of bcl-2 with decreased levels in 32% of cases. BclxL expression was comparable in all tissues examined. The pro-apoptotic protein bax was expressed at lower levels in carcinomas than in adenomas, whereas bak and bclx were expressed in the same order of magnitude in all tissues examined. In contrast, thyroid carcinoma cell lines exhibited a relatively strong expression of bclxL, but a weak expression of bcl-2. In all four cell lines, the amounts of the pro-apoptotic proteins bax, bak and bclx were higher than in most tumor tissues. Our data show that in thyroid tumors expression of members of the bcl-2 protein family is not uniform. Rather, the expression pattern of pro- and anti-apoptotic proteins in thyroid tumors is heterogeneous. This may, at least in part, reflect the futile attempt of tumor cells to counterbalance the action of growth-promoting factors in thyroid tumor-igenesis.
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PMID:Expression of apoptosis-related proteins in thyroid tumors and thyroid carcinoma cell lines. 898 Sep 94

bcl-2 is one of a family of genes that control the apoptotic threshold of a cell. bcl-2 protein and its anti-apoptotic homologue, mcl-1, with the pro-apoptotic protein, bax, are thought to function by forming homo- and heterotypic dimers that then control the progression to apoptosis. p53 is also involved as a down-regulator of bcl-2 and a promoter of bax. To determine the effect of these apoptotic mechanisms, we used immunohistochemistry to determine the prognostic significance of the expression of bcl-2, mcl-1, bax and p53 in primary and recurrent cervical cancer. Tissues from 46 patients with primary cervical cancer and 28 women with recurrent carcinoma were stained for bcl-2, mcl-1, bax and p53. Kaplan-Meier survival analysis was performed using the log-rank test for differences between groups. In the primary disease group, positive staining for bcl-2 was associated with a better 5-year survival (bcl-2 +ve, 84% vs bcl-2 -ve, 53%, P = 0.03). Positive staining for p53 was associated with a survival disadvantage (p53 +ve, 4-year survival 38% vs p53 -ve, 4-year survival 78%, P = 0.02). mcl-1 and bax staining were not useful as prognostic indicators in primary disease. No marker was prognostic in recurrent disease. Positive bcl-2 staining defines a group of patients with primary disease with a good prognosis. p53, an activator of the bax promoter, identifies a group with a worse outcome. In recurrent disease, none of the markers reflected prognosis.
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PMID:Prognostic significance of the bcl-2 apoptotic family of proteins in primary and recurrent cervical cancer. 968 95

Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.
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PMID:Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP). 1046 46

To test the hypothesis that the aging mammalian heart and brain might have increased vulnerability to acute stress, DNA fragmentation was studied after hypoxia-reoygenation in young adult (6 months) and old (22-24 months) F344 rats. Heart and brain tissue were examined at the following time points: 30, 60, or 90 min of hypoxia (H, 5% O2, 95% N2) plus 2 h of reoxygenation (R, room air, 21% O2). With increasing duration of hypoxia preceding the reoxygenation, the extent of DNA fragmentation (in situ terminal dUTP nick end labeling, TUNEL, positive cells) was progressively higher in both age groups, greater in the old compared to that of the young adult rat. The levels of the anti-apoptotic proteins bcl-2 and bcl-xL, were similar in young and old at baseline and tended to increase in both age groups after hypoxia/reoxygenation. The pro-apoptotic protein, bax, was higher at baseline in the old; it rose after hypoxia/reoxygenation in the young adult heart and brain, but was unchanged in the old heart and was decreased in the old brain. The ratios of bcl-2/bax and of bcl-xL/bax were higher in the old heart and brain compared to that in the young adult after hypoxia/reoxygenation. Thus, compared to that of the young adult, the heart and brain of the old rat have lower thresholds and are more vulnerable to injury induced by hypoxia/reoxygenation, despite rapid and heightened expression of the anti-apoptotic proteins bcl-2 and bcl-xl. This could be due partly to the age-associated increase in the basal expression of the pro-apoptotic protein bax, as well as possibly other factors.
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PMID:Influence of age on hypoxia/reoxygenation-induced DNA fragmentation and bcl-2, bcl-xl, bax and fas in the rat heart and brain. 1065 80

The regulation of apoptosis in the syncytiotrophoblast is of particular interest because this is the only true syncytial epithelium in human cell biology. Nuclei characteristic of apoptotic cells have been localized to this syncytium especially in association with fibrin-containing fibrinoid deposits. The factors responsible for regulating cell death-like features in the trophoblast syncytium are unknown. We tested the hypothesis that fibrin was required for trophoblast apoptosis. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP end-labelling) staining to detect DNA fragmentation typical of apoptosis was performed in term human placentae revealing labelled nuclei associated with fibrin-type fibrinoid, as well as labelled nuclei in discrete areas of syncytiotrophoblast without fibrin. We also hypothesized that members of the BCL-2 family of apoptosis-associated proteins contribute to the regulation of syncytiotrophoblast apoptosis. To identify members of this protein family that might regulate trophoblast apoptosis, we assessed expression of three important members of the bcl-2 gene family. We used immunohistochemistry with monoclonal antisera against human BCL-2 and polyclonal antisera against human BAX and BAK to study paraffin-embedded sections of human term placentae (n=5) from uncomplicated pregnancies. The anti-apoptotic BCL-2 protein was expressed throughout the syncytium of normal villi with much less staining in cytotrophoblast. Staining was also seen adjacent to fibrin deposits and in syncytium overlying fibrin deposits. Expression of the pro-apoptotic BAX protein was undetectable in the syncytiotrophoblast, was expressed in rare cytotrophoblast and was prominent in connective tissue and perivascular cells within the villous core. Localization of a second pro-apoptotic protein, BAK, revealed immunoreactivity in isolated areas of intact syncytium of normal villi. Additionally, fibrin deposits were associated with intense BAK staining in both syncytiotrophoblast and cytotrophoblast. From these data, we speculate that modulation of BAK expression is one factor regulating apoptosis in human trophoblast.
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PMID:Expression of BCL-2, BAX and BAK in the trophoblast layer of the term human placenta: a unique model of apoptosis within a syncytium. 1083 71

This review examines the role of 1alpha,25(OH)(2)D(3) (1,25D) and the vitamin D(3) receptor in growth regulation of normal and transformed mammary epithelial cells. 1,25D exerts both anti-proliferative and pro-apoptotic functions in transformed mammary cells such as MCF-7. The anti-proliferative effects of 1,25D have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21, p27, cyclins and Rb. The pro-apoptotic effects of 1,25D involve alterations in the relative ratios of the bcl-2 family members which regulate mitochondrial integrity. In MCF-7 human breast cancer cells, 1,25D mediated apoptosis is associated with translocation of the pro-apoptotic protein Bax to the mitochondria, generation of reactive oxygen species, dissipation of the mitochondrial membrane potential and release of cytochrome c. These mitochondrial events trigger apoptosis in a caspase-independent manner, since caspase inhibitors do not rescue 1,25D treated cells from death. The potential role of 1,25D in growth and differentiation of normal mammary epithelial cells has been examined in VDR null mice. Initial data indicates a significant decrease in ductal differentiation in VDR null mice compared to age matched wild type mice, reflected as an increased number of undifferentiated terminal end buds in the VDR null mouse. These data suggest that 1,25D promotes differentiation during early mammary gland development. In summary, our studies suggest an expanding role for the vitamin D(3) endocrine system in control of proliferation, differentiation and apoptosis of mammary epithelial cells.
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PMID:Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. 1117 38

Bcl-2 protein together with the pro-apoptotic protein bax, are thought to function by forming homo- and heterotypic dimers which control the progression to apoptosis. In this immunohistochemical study we investigated the expression of bcl-2 and bax apoptosis related proteins in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix. Twenty-four cervical intraepithelial neoplasias grade 1-2 (CIN I/II), 38 grade 3 (CIN III), and 53 invasive squamous cell carcinomas (ISCC) were investigated by immunohistochemical staining for bcl-2 and bax protein. Bcl-2 immunoreactivity was found in five of the 24 CIN I/II cases (20.8%), 18 of 38 CIN II cases (47.4%) and nine of 53 ISCC cases (17%). The positivity for CIN III was significantly higher than for CIN I/II or ISCC (p=0.0351 and p=0.0018, respectively). The percentage of bax immunopositivity was somewhat higher in CIN III than in CIN I/II but this slight difference was not statistically significant. Correlation of the immunostaining results with tumor grade revealed a significant difference for bcl-2 which was more frequently immunopositive in well-differentiated tumors than in poorly-differentiated tumors. There was no significant relation between bax expression and tumor differentiation. Our results suggest that alterations of bcl-2 and bax expression may occur as a relatively early event in cervical tumorigenesis.
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PMID:Expression of bcl-2 and bax in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix. 1119 41

We have analyzed the expression of the anti-apoptotic proteins bcl-2, bcl-xl and that of bax, a pro-apoptotic protein, in human WHO grade II astrocytomas (LGA) and WHO grade IV glioblastoma multiforme (GBM). Tumors were obtained immediately after surgical resection and were analyzed by immunohistochemistry (IHC), laser confocal microscopy (LCM) and immunoblots. Both IHC and immunoblot analysis indicated that the expression of bcl-xl was not significantly different between LGA and GBM. IHC indicated that the expression of bcl-2 was inversely correlated to the grade of the tumors (i.e more cells were bcl-2 positive in LGA than in GBM) while the expression of bax was unaffected by the grade of the tumor. In contrast, immunoblots revealed a parallel increase in the expression of bcl-2 and bax from the low to high grade tumor, suggesting a co-regulation of the expression of these two proteins during tumoral progression. Confocal analyses provide us with another possible level of complexicity in the regulation of apoptosis in these tumors, as these markers exhibited different subcellular localizations: bcl-2 was strictly associated with mitochondria and bcl-xl was present in both cytosolic and mitochondrial compartments while bax was found essentially in the cytosol of the tumoral cells. Taken together, our data suggest that the role of bcl-2 related proteins could be regulated at different levels in human astrocytomas (expression, subcellular localization, antigen exposure ...) which should be studied by different techniques.
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PMID:Expression of bcl-2, bax and bcl-xl in human gliomas: a re-appraisal. 1150 12

Bcl-2 family proteins play a critical role in the regulation of cell survival by controlling the activation of the cell death executing caspase machinery. Recent work demonstrated that they also provide a link between growth factor signaling and cell survival control. Raf-1 has been identified initially as an essential component of the mitogenic Ras-Raf-MEK-ERK cascade. However, expression of oncogenic Raf-1 also efficiently suppresses apoptotic cell death. This process requires mitochondrial translocation of Raf-1 which can be achieved either by co-expression of the anti-apoptotic protein Bcl-2 or by fusion with the transmembrane domain of the yeast outer mitochondrial membrane protein Mas 70p. It is currently unclear how mitochondrial Raf-1 prevents apoptosis. One possible mechanism involves the phosphorylation of the pro-apoptotic protein Bad resulting in the restoration of Bcl-2 function. Alternatively, the role of Bcl-2 could be limited to the mitochondrial translocation of Raf-1 and survival signaling by Raf-1 is Bcl-2 independent. To test for the mutual requirement of Raf-1 and Bcl-2 in apoptosis suppression the individual proteins were singly tested for survival activity in a genetic background which precludes the expression of the other. The results obtained in these studies demonstrate that ablation of Raf-1 or Bcl-2 expression in fibroblast cells significantly increases the sensitivity towards doxorubicin induced cell death. Reversion of the mutant phenotype could be achieved in either case by introducing a functional bcl-2 gene or a mitochondria targeted version of oncogenic Raf-1, demonstrating that each protein by itself is sufficient to confer protection. Our data thus suggest the existence of two separate pathways of survival signaling at the mitochondria controlled either by Bcl-2 or by Raf-1.
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PMID:Independent control of cell survival by Raf-1 and Bcl-2 at the mitochondria. 1152 Nov 92


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