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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of bcl-2 was studied in normal ovaries and in ovarian tumours by immunohistochemical analysis. Normal epithelium was strongly stained in all nine examined ovaries. In comparison, all tumour groups showed a substantially decreased tumour cell expression of the same order of magnitude. Thus, benign tumour cells were weakly stained in two and unstained in two samples, while the remaining eight showed strong expression. Of ten borderline samples, one was unstained and five had weakly and four strongly bcl-2 positive tumour cells. Finally, 24 of 50 malignant tumours showed strong staining, while weak or no expression in tumour cells was found in 16 and 10 samples respectively. The reduced staining deviated significantly from normal ovary for both borderline (P = 0.02) and malignant groups (P = 0.01). Tumour cell staining with the bcl-2 antibody was significantly reduced when tumour mass had to be left behind compared with those with no visible remaining tumour (P = 0.03 and 0.003 for weakly and strongly stained tumours respectively). The expression of bcl-2 in malignant tumour cells was inversely correlated with the expression of p53. Bcl-2 expression was correlated with survival with significantly reduced survival in weakly (P = 0.02) and unstained (P < 0.001) groups compared with those patients having strongly stained malignant tumour cells. This correlation between the presence of bcl-2 and survival was maintained in the subgroups of patients with advanced disease or with residual tumour bulk and was also the case in patients having p53-positive tumours. Our results indicate an inhibitory role of bcl-2 in development and progression of ovarian tumours.
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PMID:Expression and prognostic significance of Bcl-2 in ovarian tumours. 757 91

Using a highly tumorigenic human breast cancer model (Ha-ras-transfected MCF7 cell line) we analyzed the efficacy of the differentiation-inducing agent sodium phenylacetate (NaPA), both in vitro and in vivo. NaPA-treated MCF7ras cells showed dose-dependent growth inhibition from 2.5 to 15 mM without apparent toxicity. Western blot analysis showed a Bcl-2 down-regulation after 48 h treatment with 5 mM NaPA, together with apparition of apoptotic nuclei by DAPI staining. Mice bearing MCF7ras xenografts (n = 40) were treated for 2 weeks through s.c.-delivering osmotic pumps, followed by 6 weeks of daily i.p. NaPA administration. After 3 weeks, the treated tumors showed growth arrest without regression for the whole observation time, e.g., 12 weeks. Immunohistochemical analysis showed Bcl-2 down-regulation and differentiation patterns: decrease of Ki-67 and increase of steroid receptors (estrogen and progesterone receptors) compared to controls. Cells cultured from treated tumors (II.b) displayed pseudotrabecular disposition as MCF7ras cells treated in vitro. They also showed a higher NaPA sensitivity, together with 70% Bcl-2 down-regulation as compared to the derived cells of untreated tumors (II.a). When reinjected into nude mice, II.b cells induced only one poorly vascularized, noninvasive tumor (8%) with lower proliferation index, 100% progesterone receptor positive cells, and 35% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei, as compared to 100% induction of highly vascularized and invasive tumors with 3% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei induced by II.a cells.
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PMID:Sodium phenylacetate induces growth inhibition and Bcl-2 down-regulation and apoptosis in MCF7ras cells in vitro and in nude mice. 758 64

The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involves antioxidant activity. The involvement of free radicals in ischemia/reperfusion injury to neural cells has led us to investigate the effect of Bcl-2 in a model of delayed neural cell death. We have examined the survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of glucose (chemical hypoxia/aglycemia). After 30 min of treatment, no loss of viability was evident in control or bcl-2 transfectants; however, Bcl-2-expressing cells were protected from delayed cell death measured following 24-72 h of reoxygenation. Under these conditions, the rate and extent of ATP depletion in response to treatment with cyanide in the absence of glucose and the rate of recovery of ATP during reenergization were similar in control and Bcl-2-expressing cells. Bcl-2-expressing cells were protected from oxidative damage resulting from this treatment, as indicated by significantly lower levels of oxidized lipids. Mitochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment. These results indicate that Bcl-2 can protect neural cells from delayed death resulting from chemical hypoxia and reenergization, and may do so by an antioxidant mechanism. The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment of neuropathologies involving oxidative stress, including focal and global cerebral ischemia.
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PMID:Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. 759 37

Bcl-2 protooncogene, originally discovered at the chromosomal breakpoint of the t(14;18) in follicular lymphoma, is known to regulate the process of programmed cell death or apoptosis. The inhibition of apoptosis is thought to be one of the mechanisms involved in the development of tumors. To investigate the possible association of bcl-2 protooncogene with the tumorigenesis of neuroblastomas, the authors examined bcl-2 expression by immunohistochemistry in 49 neuroblastomas and 7 ganglioneuromas. The distribution of apoptotic cells was also examined by the TUNEL method (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Bcl-2 oncoprotein was detected in the cytoplasm in 40 of 49 neuroblastomas (81.6%). There was no correlation between bcl-2 oncoprotein expression and the clinical features of neuroblastoma. The incidence of bcl-2-positive tumors in ganglioneuroma was significantly lower than that in neuroblastoma (28.6%) (P < .01). TUNEL stained the nuclei of tumor cells in 11 of 34 (32.4%) neuroblastomas. TUNEL-positive cells tended to be located around calcifications in neuroblastomas in patients less than 1 year old. Examination of serial sections showed that apoptotic cells were distributed in the area where bcl-2 oncoprotein was not expressed. What we have observed indicates that apoptosis of neuroblastoma cells may be regulated by bcl-2 expression. Our observations suggest that the survival of neuroblastoma cells might be promoted by bcl-2 expression and that bcl-2 might be associated with the tumorigenesis of neuroblastomas.
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PMID:Bcl-2 oncoprotein expression and apoptosis in neuroblastoma. 766 11

Mad is a bHLH/Zip protein that, as a heterodimer with Max, can repress Myc-induced transcriptional transactivation. Expression of Mad is induced upon terminal differentiation of several cell types, where it has been postulated to down-regulate Myc-induced genes that drive cell proliferation. Here we show that Mad also blocks transformation of primary rat embryo fibroblasts by c-Myc and the activated c-Ha-Ras oncoproteins. Mad mutants lacking either the basic region, the leucine zipper, or an intact NH2-terminal protein interaction domain fail to inhibit Myc-Ras cotransformation. These results indicate that the repression of cotransformation requires DNA-binding and is mediated by multiple protein-protein interactions involving both Max and mSin3, a putative mammalian corepressor protein. With increasing amounts of the cotransfected myc gene, the numbers of transformed foci are reduced and the ability of Mad to inhibit focus formation is attenuated. Moreover, cell lines derived from such foci constitutively express both Myc and Mad proteins. Whereas Bcl-2 can significantly increase the numbers of transformed foci by enhancing the survival of myc-ras-transfected cells, it does not counteract the repressive effects of Mad on transformation, suggesting that Mad affects the growth properties rather than the viability of cells. Taken together, our results demonstrate that Mad is capable of antagonizing the biological effects of Myc and thereby suggest that Mad could function as a tumor suppressor gene.
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PMID:Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. 766 17

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
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PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

Bcl-2 expression has been evaluated immunocytochemically in a series of 33 medullary thyroid carcinomas (MTC) with long-term (mean, 10.3 years) follow-up. Twenty-six of 33 cases showed intense bcl-2 immunoreactivity in more than 25% neoplastic cells. Bcl-2 immunoreactivity did not correlate with several clinicopathologic parameters including sex and age of the patients, sporadic or familial disease, tumor size and stage, amount of amyloid stroma, and immunoreactivity for calcitonin, chromogranin A, proliferating cell nuclear antigen (PCNA), N-myc, and p53. Lack of bcl-2 immunoreactivity, however, correlated significantly (P = .0001) with a shorter survival. Indeed, the seven patients with tumors devoid of bcl-2 immunoreactivity all died of disease within 8 years from the diagnosis. In multivariate analysis, lack of bcl-2 immunoreactivity was an independent predictor of worse prognosis (P = .001 for disease-free survival and P = .0001 for overall survival). None of the other clinicopathologic variable investigated proved to be an independent prognostic parameter. It is concluded that down-regulation of bcl-2 expression in MTC may identify a subset of tumors with a more aggressive clinical course.
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PMID:Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. 767 94

Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of interlekin-3 (IL-3) induces G1 arrest, and irradiation in the absence of IL-3 results in rapid apoptotic cell death. Both of these end points are dependent on p53. Transient removal of IL-3 at the time of irradiation results in decreased clonogenic survival of irradiated cells. The removal of IL-3 results in a failure of the irradiated cells to arrest at the G1 checkpoint, despite induction of p53 and p21WAF1/CIP1, and then the cells enter S-phase where they undergo apoptosis. There are no cytokine-related changes in Bcl-2, Bax, or Bcl-x protein levels that could account for the modulation of G1 arrest versus apoptosis by growth factors. In contrast, rapid p53-independent alterations of basal levels of gadd45 and p21WAF1/CIP1 expression are linked to IL-3 withdrawal, suggesting a potential mechanism for this modulation. Constitutive activation of cytokine-like pathways with induced expression of v-Src or activated c-Raf inhibits the radiation-induced apoptosis and the alterations in p21WAF1/CIP1 and gadd45 expression. These observations suggest additional molecular mechanisms that can contribute to the development of radioresistance and resistance to apoptosis during tumorigenesis and provide an explanation for the observed lack of p53 mutations in some tumor types. In addition, these data suggest that oncogenic changes occurring during multistep tumorigenesis could be classified as those that either enhance or decrease apoptosis tendencies.
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PMID:Growth factor modulation of p53-mediated growth arrest versus apoptosis. 769 49

Apoptosis is a required event in maintaining kinetic homeostasis within continually renewing tissues such as skin. However, no systematic study of the apoptotic process in epidermal keratinocytes of the skin has been performed. In this report, we examined the expression of proteins associated with promoting (Fas) or preventing (Bcl-2, Bcl-x, CD40) apoptosis in the normal, psoriatic, and malignant keratinocyte. Immunohistochemical staining and flow cytometry analysis revealed that normal cultured keratinocytes express low levels of Fas, CD40, and Bcl-x that was enhanced by cytokines including gamma-interferon (IFN-gamma) and a phorbol ester tumor promoter, TPA. Only faint Bcl-2 staining was detected in cultured keratinocytes exposed to IFN-gamma and TPA compared with the prominent expression of Bcl-x. Biopsies of normal skin, psoriatic plaques, and basal cell carcinomas were examined to extend the in vitro observations. Immunohistochemical staining revealed that while keratinocytes in normal epithelium express low to absent levels of Fas and Bcl-x, psoriatic keratinocytes expressed significantly higher levels of Fas and Bcl-x. In contrast, malignant keratinocytes in basal cell carcinomas expressed high levels of Bcl-2, but minimal Bcl-x, and no Fas. Immunoblot analysis revealed that the long form of Bcl-x (Bcl-xI), which prevents apoptosis in lymphocytes, is expressed by cultured keratinocytes and psoriatic plaque keratinocytes. We conclude that normal cytokine-activated keratinocytes can express an apoptotic (Fas) and an anti-apoptotic protein (Bcl-x). The overexpression of Bcl-x in psoriasis, or Bcl-2 in basal cell carcinomas, may contribute to the longevity of these cells by blocking the normal apoptotic process involved in the terminal differentiation program of epidermal keratinocytes.
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PMID:Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo. 774 3

Bcl-2 oncoprotein, a member of a new category of oncogenes associated with the regulation of programmed cell death (apoptosis), has been considered to be involved in biological processes such as tumorigenesis and tumor development. To determine the role of bcl-2 oncoprotein in lung cancer, we preliminarily examined the expression of this protein in various histological types. Immunohistochemical staining using monoclonal bcl-2 oncoprotein antibody was performed in surgically resected frozen specimens. Bcl-2 staining was seen in nine of 13 small cell lung cancers (69%), while only 18 out of 69 non-small cell lung cancers (26%) expressed bcl-2 oncoprotein, showing a significantly increased incidence of bcl-2 oncoprotein expression in the former histological type. Considering the greater aggressiveness of small cell lung cancer compared to non-small cell lung cancer, the possibility exists that the high prevalence of bcl-2 oncoprotein expression in small cell lung cancer is closely associated with tumorigenesis and tumor development.
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PMID:High prevalence of bcl-2 oncoprotein expression in small cell lung cancer. 776 30


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