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)

The S49.1 and WEHI7.2 murine lymphoid cell lines have been used extensively as models for investigations of programmed cell death ("apoptosis") induced by glucocorticoids such as dexamethasone. Infection of these thymus-derived T-cell lines with a recombinant retrovirus encoding the human M(r) 26,000 Bcl-2 oncoprotein resulted in marked resistance to DEX-mediated cell death and DNA degradation into oligonucleosomal fragments, without interfering with the ability of dexamethasone to suppress cellular proliferation and without lowering levels of glucocorticoid receptors. In contrast, high levels of p26-Bcl-2 production did not block cell killing and DNA fragmentation induced by H2O2, suggesting that the Bcl-2 impairs some but not all pathways for cell death in S49.1 and WEHI7.2 cells that are associated with the DNA fragmentation pattern typical of apoptosis. S49.1 and WEHI7.2 cells infected with bcl-2 but not control retrovirus also exhibited increased resistance to cell killing and DNA fragmentation induced by a wide variety of reagents, including the calcium ionophore ionomycin, the phorbol ester tetradecanoylphorbol acetate, the dihydrofolate reductase inhibitor methotrexate, the antimetabolite 1-beta-D-arabinofuranosylcytosine, and the microtubule inhibitor vincristine. These findings provide evidence that p26-Bcl-2 interferes with a pathway for cell death that is activated by multiple drugs used for the treatment of cancer.
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PMID:bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. 139 46

Mice carrying ablated coding regions of the bcl-2 alpha and bcl-2 beta transcripts have been made. bcl-2-/- mutants are smaller but viable, although about half of them die by 6 weeks of age. As shown earlier with somatic bcl-2 gene-targeted mice, the number of lymphocytes markedly decreased within few weeks after birth while other hematopoietic lineages remained unaffected. Among lymphocytes, CD8+ T cells disappeared most quickly followed by CD4+ T cells, whereas B cells were least affected. bcl-2-/- lymphocytes, however, could respond normally to various stimuli including anti-CD3, Con A, phorbol 12-myristate 13-acetate plus ionomycin, interleukin 2, lipopolysaccharide, and anti-IgM antibody. Abnormalities among nonlymphoid organs include smaller auricles, hair color turning gray at 4-5 weeks of age, and polycystic kidney disease-like change of renal tubules. These results suggest that Bcl-2 may be involved during morphogenesis where inductive interactions between epithelium and mesenchyme are important such as in the kidneys, hair follicles, and perichondrium of auricles. Surprisingly, the nervous system, intestines, and skin appear normal despite the fact that these organs show high levels of endogenous Bcl-2 expression in normal mice.
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PMID:Targeted disruption of Bcl-2 alpha beta in mice: occurrence of gray hair, polycystic kidney disease, and lymphocytopenia. 817 Sep 72

When established in culture, human neuroblastoma cell lines typically are comprised of heterogeneous cellular subpopulations, including neuroblastic (N-type), substrate-adherent (S-type), and intermediate (I-type) cells that can be distinguished by their characteristic morphologies and expression of differentiation-associated antigens. Here we examined the relative levels of the Bcl-2 oncoprotein in 15 clones derived from four different neuroblastoma cell lines. Among six clones isolated from the SK-N-SH line, levels of p26-Bcl-2 correlated with morphology and differentiation markers with the hierarchy of bcl-2 expression being: N-type cells > N/I-type > I-type > S-type. Furthermore, stimulation of one of the N-type clones, SH-SY5Y, with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, induced differentiation toward a more neuronal-like phenotype and resulted in a 5- to 10-fold elevation in the relative levels of Bcl-2 protein. High relative amounts of p26-Bcl-2 protein were also found in an N-type clone derived from the SMS-KCN line. In two N-type clones derived from the LA-N-1 line, however, levels of Bcl-2 protein were only moderately elevated, and in one N-type clone from the SK-N-BE(2) line the levels of Bcl-2 protein were low. Thus, high relative levels of Bcl-2 oncoprotein are not a universal feature of N-type cells (three of six clones tested). In contrast, all 5 of the S-type clones evaluated contained relatively low levels of Bcl-2 protein, suggesting that these cells (which may represent embryonic precursors of Schwann, glial, and melanocytic cells) do not typically express the bcl-2 gene at high levels. Consistent with this inverse correlation between Bcl-2 protein levels and S-type characteristics, stimulation of an I-type clone derived from the SK-N-BE(2) line with 5-bromodeoxyuridine was accompanied by an accumulation of S-type cells in these cultures, decreased Bcl-2 protein, diminutions in the neuronal markers neurofilament-M and neuron-specific enolase, and an increase in the relative levels of the S-type marker proteins vimentin and beta-2-microglobulin. Conversely, stimulation of this I-type clone with retinoic acid resulted in an accumulation of N-type cells (which are thought to represent embryonic precursors of sympathetic neurons), decreased vimentin and beta-2-microglobulin, increased neurofilament-M, and a marked elevation in p26-Bcl-2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of Bcl-2 oncoprotein levels with differentiation of human neuroblastoma cells. 840 88

Normal peripheral blood B lymphocytes undergo spontaneous apoptosis in vitro, and this process is regulated positively and negatively by several immunomodulatory stimuli. We have shown previously that Bcl-2 protein levels are unaltered by these factors, suggesting a Bcl-2-independent regulation of apoptosis in this system. Here, we have investigated the possibility that the three recently identified Bcl-2 homologues, Bax, Bcl-x, and Mcl-1, could be involved instead. Freshly isolated cells expressed both Bax and Mcl-1 protein, but only low levels of Bcl-xL and no detectable Bcl-xS, as determined by Western blot analysis. Upon culture of cells with apoptotic or survival stimuli, Bax and Bcl-xL protein levels remained relatively unchanged. By contrast, Mcl-1 levels decreased markedly in cells undergoing apoptosis in medium and, even more dramatically, after treatment with the apoptotic stimuli transforming growth factor beta 1 and forskolin. This decrease was rapid and preceded cell death. Furthermore, all the survival stimuli tested (interleukin 4, anti-IgM antibodies, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) prevented the decline in Mcl-1 levels. This striking correlation between cell survival and Mcl-1 expression in peripheral blood B cells suggests the possible involvement of Mcl-1, instead of Bcl-2, in the regulation of apoptosis in these cells. The present study is the first one linking this novel Bcl-2 homologue to the control of cell death in normal cells.
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PMID:Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes. 854 71

c-Raf-1 (Raf-1) is a central component of signal transduction pathways stimulated by various growth factors, protein kinase C, and other protein kinases. Raf-1 activation is thought to be initiated at the plasma membrane after its recruitment by Ras. Raf-1 activation is associated primarily with proliferation and cell survival, but it has also been implicated in apoptosis. Raf-1 has also been shown to form complexes with both R-Ras and Bcl-2, raising the possibility that this component of cellular Raf-1 plays a role in apoptosis. Recently, taxol was reported to induce Bcl-2 phosphorylation and inactivation. We have previously demonstrated Raf-1 activation following taxol in MCF7 cells. We now present evidence that taxol fails to stimulate either apoptosis or phosphorylation of Bel-2 in the absence of Raf-1. Moreover, Raf-1 activation by taxol coincided with Bel-2 phosphorylation, showing similar dose and time dependence. Thus, our data support a role for a distinct subcellular component of Raf-1, which is taxol but not phorbol myristate acetate sensitive, in mediating an apoptotic pathway involving Bc1-2.
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PMID:Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. 862 May 3

The regulatory mechanism of Bcl-2 protein expression was investigated in SH-SY5Y cells, the human neuroblastoma cell line that expresses natively Bcl-2 proteins. WHen the cells were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or retinoic acid, the level of Bcl-2 protein was increased compared with the control. These effects were inhibited by pretreatment with a protein kinase C (PKC) inhibitor, staurosporine or calphostin C. The level of Bcl-2 protein was also increased by treatment with carbachol, a muscarinic acetylcholine receptor (mAChR) agonist, and the effect were also inhibited by pretreatment with staurosporine or calphostin C. An addition, a carbachol-induced increase in Bcl-2 protein levels and a transient elevation of [Ca2+]i were inhibited by pretreatment with 4-DAMP (4-diphenylacetoxy-N-methylpiperidine), an m3 mAChR antagonist. In contrast, the level of Bcl-2 protein was decreased by treatment with dibutyryl cAMP (diBu-cAMP), forskolin, or cholera toxin, and the effects of diBu-cAMP were inhibited by pretreatment with a protein kinase A (PKA) inhibitor, H-89. From these results, we suggest that the expression of Bcl-2 proteins is regulated by PKC and PKA in positive and negative manners, respectively, in SH-SY5Y cells. Furthermore, the nucleosomal DNA fragmentation induced by serum depletion for 4 h was observed in SH-SY5Y cells when the level of Bcl-2 protein was down-regulated by treatment with 1 mM diBu-cAMP for 3 days, although the DNA fragmentation by serum depletion for 4 h was not observed in nontreatment cells, indicating that Bcl-2 proteins whose expression is regulated by PKC and PKA play important roles in serum depletion-induced apoptosis.
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PMID:Regulation of Bcl-2 protein expression in human neuroblastoma SH-SY5Y cells: positive and negative effects of protein kinases C and A, respectively. 866 83

Dimethyl sulfoxide (DMSO), which induces differentiation of myeloid cells, was found to cause apoptosis in human leukemic U937 cells. Apoptosis was assessed by DNA electrophoresis and flow cytometry. The time needed to induce apoptosis varied from a few hours to 2-3 days, depending on the concentration of DMSO used. The plasma membrane remained intact long after DNA fragmentation had occurred. DMSO-induced apoptosis was inhibited by zinc ions and, to a lesser extent, by the protein kinase C activator: phorbol 12-myristate 13-acetate (PMA). Cycloheximide and actinomycin D did not prevent DMSO-induced apoptosis, showing that U937 cells do not require protein or RNA synthesis to undergo apoptosis. DMSO induced apoptosis despite the expression of the anti-apoptotic Bcl-2 protein in U937 cells. The amount of Bcl-2 remained unchanged during DMSO-induced apoptosis.
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PMID:Dimethyl sulfoxide-induced apoptosis in human leukemic U937 cells. 872 51

During early pregnancy, the uterine endometrium responds to an implanting blastocyst with the extensive growth and differentiation of decidualization. This transformation of endometrial stromal cells begins in the antimesometrial side of the uterus to form a primary decidual zone, expands to form a secondary zone in the antimesometrium, and eventually transforms stromal cells in the mesometrial region. During pregnancy, both decidual zones regress by apoptosis, leaving decidual cells in the mesometrial region to form decidua basalis and the mature placenta. Molecular mechanisms controlling cell death during blastocyst implantation and decidualization are unknown. We examined the hypothesis that progesterone and estrogen control of endometrial differentiation and eventual apoptosis involves control of bcl-2 gene family expression. Ovariectomized rats were primed with estradiol and treated with progestin (medroxyprogesterone acetate, 3.5 mg) and estradiol (200 ng) before an intrauterine stimulus to initiate decidualization. Expression of the two bax messenger RNA transcripts, 1.0 and 1.5 kilobases, was examined by Northern blot analysis after hormone treatment and decidualization, and only the 1.0-kilobase transcript was induced. After the same treatments, the expression of bcl-2, a suppressor of apoptosis, decreased. In situ analysis revealed a cell type-specific increase in bax expression after the hormonal treatment and decidualization. This increase was first seen in luminal and glandular epithelial cells and then in the periluminal stroma 24 h after intrauterine stimulation, with eventual progressive expression throughout the stroma. Expression of bcl-2 decreased after hormone treatment and decidualization. Immunohistochemical studies of Bax showed that expression of Bax protein accompanied decidualization of the stroma. Bcl-2 protein was only seen in the luminal and glandular epithelia, and its level decreased as decidualization progressed. These data indicate that the balance between bax and bcl-2 expression is altered during stromal cell differentiation. Increased expression of bax precedes nucleosomal DNA fragmentation and eventual apoptosis, which plays a significant role in placental development.
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PMID:Effect of decidualization on the expression of bax and bcl-2 in the rat uterine endometrium. 877 Sep 38

Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 micrograms/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 micrograms/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W7 (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death.
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PMID:Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. 895 Jan 93

CD6 and CD5 belong to a scavenger-receptor cysteine-rich (SRCR) super family of membrane glycoproteins that are expressed on chronic lymphocytic leukemia B (B-CLL) cells, normal T cells, and a small subset of normal B cells. CD6 configures in the membrane in relation to the cellular activation level and can act as a coreceptor for T-cell activation. We have examined a group of progressive and nonprogressive B-CLL cells. Most B-CLL cells were positive for CD6 and the expression of CD6 was increased after activation with Staphylococcus aureus Cowan I plus interleukin-2 or 12-O-tetradecanoylphorbol 13-acetate, although anti-CD6 antibodies did not increase proliferative responses to these stimuli. However, anti-CD6 stimulation was found to protect against anti-IgM-induced apoptosis in B-CLL. bax(alpha) upregulation and bcl-2 downregulation were found in anti-IgM- and glucocorticoid (GCC)-induced apoptotic cells, respectively. Furthermore, CD6 cross-linking downregulated bax(alpha) mRNA levels in anti-IgM-treated cells, resulting in an increased bcl-2/bax(alpha) ratio. CD6 activation also prevented bcl-2 mRNA downregulation and apoptosis induced by GCC in one of six GCC-sensitive patients. These data suggest that an interaction between CD6 and its ligand might contribute to B-CLL survival through the modulation of the Bcl-2/Bax ratio.
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PMID:CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B cells from apoptosis induced by anti-IgM. 910 2


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