UNIPROT:P10415 - FACTA Search

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

The epidermal keratinocyte cell line Pam212 undergoes spontaneous apoptosis in culture, providing an in vitro model for the early steps of epidermal differentiation. Pam212 cells exhibit characteristics of basal keratinocytes, committed for the transition to the spinous layer of the epidermis. Bcl-2 can regulate the differentiation of these cells by negatively regulating several genes that have been implicated in apoptosis. We show evidence that a serine protease activity, secreted by the Pam212 cells, could induce apoptosis in Pam212 and several other cell lines. This activity might be regulated via the bcl-2 pathway. We suggest that this serine protease could either directly, via binding and/or cleavage of a serine protease-activated receptor, or indirectly, via the cleavage of an unknown protein, activate the signaling for apoptosis in Pam212 cells. Alternatively, this secreted serine protease could reenter the cell and start a proteolytic cascade reaction that leads to cell death. This is based on the induction of apoptosis in several cell lines by the partially purified serine protease activity, and the minimal effect of protein synthesis inhibition on Pam212 apoptosis. We propose that in vivo, a two-step mechanism controls keratinocyte apoptosis and differentiation. The basal cells of the epidermis contain all of the necessary proteins required for apoptosis, as well as the repressor protein Bcl-2. As Bcl-2 levels go down, the cells commit to terminal differentiation. A serine protease, secreted from these cells, then induces the death process. This second step enables the cells to undergo apoptosis and continue the process of terminal differentiation.
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PMID:A secreted serine protease can induce apoptosis in Pam212 keratinocytes. 754 2

Group I and Epstein-Barr virus-negative Burkitt's lymphoma cell lines and the B104 lymphoma cell line which expresses a phenotype of immature B cells undergo apoptosis after cross-linking of their surface Ig receptors or after exposure to a calcium ionophore. We show here that tumor necrosis factor (TNF)-alpha protects these B cell lines against Ca(2+)-dependent apoptosis. Protection was associated with up-regulation of bcl-2 mRNA and protein expression. The increase of Bcl-2 expression induced by TNF-alpha was inhibited by chelerythrine, a specific inhibitor of protein kinase C (PKC), suggesting that Bcl-2 expression was dependent on PKC activation. Furthermore, we show that phorbol esters and cyclosporin A (CsA), which prevent Ca(2+)-dependent apoptosis, up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expression is controlled by calcineurin since we have shown that FK506 but not rapamycin had the same effect on Bcl-2 expression, whereas okadaic acid, an inhibitor of phosphatases 1, 2A and 2C, was ineffective. These data provide direct evidence that TNF-alpha prevents Ca(2+)-dependent apoptosis by a Bcl-2-dependent mechanism mediated by PKC.
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PMID:Tumor necrosis factor-alpha up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines. 754 79

Purkinje cell degeneration (pcd) is an autosomal recessive mutation in the mouse characterized by an almost complete loss of cerebellar Purkinje neurons between postnatal days 22 and 28. The pcd gene has not been identified, however, a relationship between activation of specific genes and cell death has been suggested in other models of neuronal cell death. In the present study we analyzed the expression of several candidate cell death effector genes (bax, c-fos, junB, krox-24) and a cell death repressor gene (bcl-2) in the cerebellum of pcd homozygotes and wild-type mice. At postnatal day 22, when Purkinje cells start to degenerate, levels of c-fos, junB, and krox-24 mRNA increased about 5-fold in mutants. To the contrary, the amount of bcl-2 mRNA declined and bax transcripts remained unchanged compared to wild-type animals. Immunoreactivity for c-Fos and Jun could be detected exclusively in cerebellar Purkinje neurons of pcd mice but not in wild-types, whereas the number of Bcl-2 immunopositive Purkinje cells decreased significantly in mutants. Both double labeling experiments and immunostaining of consecutive sections revealed lack of colocalization of Jun with Bcl-2. These results demonstrate an induction of members of the fos and jun family and a downregulation of antiapoptotic bcl-2 in cerebellar Purkinje neurons that are destined to die. Fos and Jun transcription factor proteins may be implicated in the regulation of bcl-2 expression and in the signal cascade leading to Purkinje cell death.
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PMID:Differential regulation of bcl-2, bax, c-fos, junB, and krox-24 expression in the cerebellum of Purkinje cell degeneration mutant mice. 756 51

All-trans retinoic acid (ATRA) increases the sensitivity of AML blast cells to cytosine arabinoside (Ara-C) or daunorubicin (DNR) when ATRA is given after drug. We have proposed that down-regulation of bcl-2 is part of the mechanism by which ATRA regulates drug sensitivity. To test this hypothesis cDNA encoding bcl-2 was transfected into cells of the continuous lines OCI/AML-2 and OCI/AML-5. Four transfectant lines were isolated; three contained transfected bcl-2 in the sense orientation (AML5-BCL2sa, AML5-BCL2sb and 2-bcl2) and one with anti-sense bcl-2(AML5-bcl2as). The presence of the transfected gene was demonstrated by Northern blot; translation of the sense transfected genes into protein was demonstrated by Western blotting. Lines with sense-oriented transfected bcl-2 were significantly less sensitive to Ara-C or H2O2 than the parental lines; the cells with anti-sense transfected genes were more sensitive than their parent but the difference did not reach statistical significance. The effect of ATRA on bcl-2 expression was compared in sense-transfected cells and their parents; by Northern blotting it was shown that the endogenous but not the transfected genes were down-regulated after ATRA exposure. The capacity of cells with transfected genes to respond to ATRA was tested by obtaining Ara-C survival curves for ATRA-treated cells. Compared to controls not exposed to ATRA, the transfected cells showed little or statistically insignificant changes in Ara-C sensitivity after ATRA treatment. We conclude that data from the transfectants provides evidence that expression of bcl-2 is a determinant of sensitivity to Ara-C and H2O2; and that the effect of ATRA on sensitivity requires the presence of bcl-2 genes in association with regulatory elements.
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PMID:Direct evidence for the participation of bcl-2 in the regulation by retinoic acid of the Ara-C sensitivity of leukemic stem cells. 756 7

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

Developing neurons die if they fail to obtain an adequate supply of neurotrophins from their targets but how neurotrophins suppress cell death is not known. Although over-expression of exogenous Bcl-2 can prevent the death of cultured neurons deprived of members of the nerve growth factor family of neurotrophins it is not known if this effect is physiologically relevant. To determine if Bcl-2 participates in the neurotrophin survival response we used antisense bcl-2 RNA to inhibit endogenous Bcl-2 expression. Here we show that brain-derived neurotrophic factor (BDNF)-dependent neurons are killed by antisense bcl-2 RNA in the presence of BDNF. However, when these neurons were supported with ciliary neurotrophic factor (CNTF) their survival was not affected by antisense bcl-2 RNA. Likewise, the survival of CNTF-dependent ciliary neurons was not affected by antisense bcl-2 RNA. Our findings suggest that Bcl-2 is required for the BDNF survival response and that alternative, Bcl-2-independent survival mechanisms operate in sensory and parasympathetic neurons exposed to CNTF.
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PMID:Role of Bcl-2 in the brain-derived neurotrophic factor survival response. 758 99

The process of programmed cell death is frequently attenuated by inhibitors of protein and RNA synthesis. This implies that gene expression is necessary for the active elimination of some cell types. Genes such as bcl-2 and bax have been implicated in the direct control of cell death, while cellular immediate-early genes (cIEGs), such as c-fos and c-jun have been repeatedly associated with neuronal degeneration. We are using the olfactory neuroepithelium as a model system to investigate the role that expression of such genes might play in cell death. The advantages of this system is that even in the adult, there is spontaneous degeneration of olfactory receptor neurons followed by their replacement by the division and differentiation of precursors. Furthermore, the receptor neurons can be induced to die synchronously by removal of the olfactory bulb or intranasal administration of toxic agents. We have generated fos-lacZ and jun-lacZ transgenic mice that can be used to assess expression of c-fos and c-jun following these various manipulations. In addition, a line of transgenic mice has been derived that express Bcl-2 under the control of the olfactory receptor protein promoter. These mice have high levels of Bcl-2 selectively in receptor neurons of the primary neuro-epithelium and vomeronasal organ. Since in some circumstances, Bcl-2 can protect against programmed cell death these mice are being assessed for neuronal turnover under basal conditions and following olfactory bulbectomy.
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PMID:The olfactory system as a model for the analysis of the contribution of gene expression to programmed cell death. 758 21

Apoptosis is a major form of cell death induced by chemotherapeutic drugs. Overexpression of the proto-oncogene bcl-2 can prevent apoptosis in various types of cells. We have constructed a HeLa S3 cell line in which the expression of bcl-2 can be controlled by the concentration of tetracycline in the medium. Using this system, we show that apoptosis induced by various cytostatic treatments could be delayed by the overexpression of bcl-2, as assayed by vital dye exclusion, apoptotic nuclei morphology, DNA histogram shift, and DNA fragmentation. Quantitative analysis revealed a hyperbolic curve when protection from apoptosis was plotted against the amount of Bcl-2. When cells were treated with aphidicolin for 12, 24, or 36 h and then replated in fresh media to assay for colony formation, the majority of cells that did not show apoptotic morphology at the time of drug removal failed to form colonies. Furthermore, Bcl-2 did not increase colony formation after 12-36 h of aphidicolin treatment. Therefore, with aphidicolin treatment, cells were committed to the death program upstream of the point of Bcl-2 action.
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PMID:BCL-2 expression delays drug-induced apoptosis but does not increase clonogenic survival after drug treatment in HeLa cells. 758 31

The inhibin-alpha gene is expressed in a tissue-specific manner, and its protein product dimerizes with one of two beta-subunits to form bioactive heterodimers. To characterize the cis-acting elements involved in directing gonad- and adrenal-specific expression of inhibin-alpha, transgenic mice were generated that carried 2.5 or 6 kilobases (kb) of the 5'-flanking region of the mouse inhibin-alpha gene driving the human bcl-2 complementary DNA. Using an antibody specific for human Bcl-2, Western blotting and immunocytochemical analyses showed that both enhancer/promoter fragments direct transgene expression to the ovary, testis, and adrenal gland. The 6-kb fragment targeted the ovarian transgene expression in interstitial cells and young corpora lutea as well as granulosa and thecal cells of secondary, antral, and preovulatory follicles. In ovaries of animals with the 2.5-kb fragment, transgene expression was also detected in interstitial cells and young corpora lutea, but only in granulosa and thecal cells from antral and preovulatory follicles. The ovarian transgene expression in animals carrying the 6-kb inhibin-alpha promoter/bcl-2 construct was stimulated by gonadotropin treatment, with greater than 10-fold increases observed 2 days after PMSG stimulation. In the testes of both types of transgenic animals, immunoreactive Bcl-2 was predominantly detected in Sertoli cells of seminiferous tubules. Sporadic expression was also observed in some interstitial cells. In the adrenal gland, reporter protein was detected in the zona fasciculata of both types of transgenic animals during adult life; however, transgene expression was detected in zona fasciculata of young (21-day-old) animals with the 6-kb, but not the 2.5-kb, promoter construct. Thus, the 2.5-kb inhibin-alpha 5'-proximal DNA sequence directs transgene expression in mature ovarian follicles and testicular Sertoli cells. In contrast, enhancer elements in the 6-kb fragment are required for expression in preantral follicles and in the adrenal of immature animals. The inhibin-alpha promoter/enhancer used here represents unique DNA sequences for ovarian-specific transgene expression and is useful for future analysis of gonadal and adrenal cell functions.
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PMID:Different 5'-flanking regions of the inhibin-alpha gene target transgenes to the gonad and adrenal in an age-dependent manner in transgenic mice. 758 11

The mechanisms of luteal regression and rescue in women are unknown but forms of programmed cell death may be involved. The proto-oncogene bcl-2 is an important inhibitor of apoptosis but has not previously been described in the human corpus luteum. Immunohistochemical localization of bcl-2 protein was investigated in human corpora lutea obtained from women undergoing surgery during endocrine monitored menstrual cycles as well as from women who had been treated with human chorionic gonadotrophin (HCG) to prolong the luteal phase. Bcl-2 was found to be localized in granulosa-lutein, theca-lutein (as identified by co-localization of P450(17)alpha-hydroxylase) and the endothelial cells around some blood vessels. Immunoblotting demonstrated the presence of a single band of approximately MW 26 kDa. There was no apparent change in either the intensity of immunostaining or the histological localization during the normal luteal phase or following treatment with human chorionic gonadotrophin. The product of the proto-oncogene bcl-2 is present in the human corpus luteum. It is unlikely that bcl-2 expression alone is responsible for prolongation of the lifespan of the corpus luteum in early pregnancy although it is possible that the action of the bcl-2 gene present is modified by changes in other members of the bcl-2 family.
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PMID:Immunolocalization of bcl-2 in the human corpus luteum. 759 40

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