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)

We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression.
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PMID:Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction. 1131 11

Signal transduction pathways that mediate neuronal commitment to apoptosis involve the nuclear factor kappa B (NF-kappaB) transcription factor. The bcl-x gene is a member of the bcl-2 family of genes that regulate apoptosis, and gives rise to two proteins, Bcl-XL and Bcl-XS, via alternative mRNA splicing. BCl-XL protein, like Bcl-2, is a dominant inhibitor of apoptotic cell death, whereas Bcl-XS promotes apoptosis. While there is high expression of Bcl-XL in the developing and adult brain, few transcriptional control elements have been identified in the bcl-x promoter. There are two functional nuclear factor-kappa B (NF-kappaB) DNA binding sites clustered upstream of the brain-specific transcription start site in the upstream promoter region of murine bcl-x. Recombinant NF-kappaB proteins bind to these sites. Also NF-kappaB overexpression, coupled with bcl-x promoter/reporter assays using a series of murine bcl-x promoter and deletion mutants, has identified the downstream 1.1kb of the bcl-x promoter as necessary for basal promoter activity and induction by NF-kappaB in support of the hypothesis that NF-kappaB can act to enhance BCl-XL expression via highly selective interactions with the bcl-x promoter, where NF-kappaB binding and promoter activation are dependent on specific DNA binding site sequences and NF-kappaB protein dimer composition. Hypoxia induces apoptosis in the hippocampus where the NF-kappaB dimers c-Rel/p50 and p50/pS0 bind to the bcl-x promoter NF-kappaB site.
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PMID:Transcriptional regulation of the BCL-X gene by NF-kappaB is an element of hypoxic responses in the rat brain. 1151 24

Chloroquine is a lysosomotropic agent that causes marked changes in intracellular protein processing and trafficking and extensive autophagic vacuole formation. Chloroquine may be cytotoxic and has been used as a model of lysosomal-dependent cell death. Recent studies indicate that autophagic cell death may involve Bcl-2 family members and share some features with caspase-dependent apoptotic death. To determine the molecular pathway of chloroquine-induced neuronal cell death, we examined the effects of chloroquine on primary telencephalic neuronal cultures derived from mice with targeted gene disruptions in p53, and various caspase and bcl-2 family members. In wild-type neurons, chloroquine produced concentration- and time-dependent accumulation of autophagosomes, caspase-3 activation, and cell death. Cell death was inhibited by 3-methyladenine, an inhibitor of autophagic vacuole formation, but not by Boc-Asp-FMK (BAF), a broad caspase inhibitor. Targeted gene disruptions of p53 and bax inhibited and bcl-x potentiated chloroquine-induced neuron death. Caspase-9- and caspase-3-deficient neurons were not protected from chloroquine cytotoxicity. These studies indicate that chloroquine activates a regulated cell death pathway that partially overlaps with the apoptotic cascade.
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PMID:Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent. 1158 24

In the mammary gland Bcl-x is the most abundant cell survival factor from the Bcl-2 family. Since Bcl-x null mice die around day 12 of embryogenesis, the relevance of this protein in organ development and function is poorly understood. In erythroid cells bcl-x gene expression is controlled by cytokines and the transcription factor Stat5 (signal transducer and activator of transcription). However, we identified that bcl-x RNA levels in mammary tissue from prolactin receptor- and Stat5-null mice were indistinguishable from wild type mice. We have proposed that Bcl-x might control the survival of mammary epithelial cells throughout pregnancy, lactation, and the early stages of involution, and we have now tested this hypothesis through the conditional deletion of the bcl-x gene from mouse mammary epithelium. Conditional (floxed) bcl-x alleles were excised from alveolar cells during pregnancy using a Cre transgene under the control of the whey acidic protein gene promoter. Deletion of the bcl-x gene from the entire epithelial compartment (ducts and alveoli) was achieved by expressing Cre-recombinase under control of the mouse mammary tumor virus long terminal repeat. The absence of Bcl-x did not compromise proliferation and differentiation of mammary ductal and alveolar epithelial cells in virgin mice and during pregnancy and lactation. However, epithelial cell death and tissue remodeling were accelerated in the bcl-x conditional knockout mice during the first stage of involution. Concomitant deletion of the bax gene did not significantly modify the Bcl-x phenotype. Our results suggest that Bcl-x is not essential during mammopoiesis, but is critical for controlled apoptosis during the first phase of involution.
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PMID:Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation. 1173 Dec 40

We have examined the effects of antisense oligonucleotides to bcl-x on the survival and chemosensitivity of CEM cells, a T-acute lymphoblastic leukemia (T-ALL) cell line. Also, we have measured the levels of Bcl-2, Bcl-x, and Bax in 20 cases of T-ALL. By 18 h after the bcl-x antisense treatment, CEM cells showed over a 75% reduction in the levels of Bcl-xL protein and over 30% decreased viable cell counts compared with cells treated with the control oligonucleotide. The combination of bcl-x antisense plus either dexamethasone or doxorubicin showed either strong synergistic or additive killing of CEM cells, respectively. These findings indicate that bcl-x antisense has cytotoxic activity and increases chemotherapy-induced cell death in CEM cells, a model for T-ALL.
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PMID:Inhibition of Bcl-xL expression sensitizes T-cell acute lymphoblastic leukemia cells to chemotherapeutic drugs. 1179 21

Constitutive nuclear factor kappaB (NF-kappaB) activity protects quiescent mature immune cells from spontaneous apoptosis. Here, we examined whether NF-kappaB exerts its antiapoptotic function in these cells through the control of Bcl-2 family proteins. Specific pharmacologic inhibitors of NF-kappaB were used to achieve total NF-kappaB inactivation in quiescent human blood lymphocytes, granulocytes, and monocytes. NF-kappaB inhibition induced drastic lymphocyte and granulocyte apoptosis, but only moderate monocyte apoptosis. T- and B-cell apoptosis was slow and associated with a gradual down-regulation of the prosurvival Bcl-2 family proteins Bcl-x(L) and Bcl-2, respectively. By contrast, granulocyte apoptosis was fast and accompanied by a rapid cellular accumulation of Bcl-x(S), the proapoptotic Bcl-x isoform that is generated from alternative splicing of the bcl-x pre-mRNA. Finally, antisense bcl-x(L) and bcl-2 knockdown in T and B cells, respectively, and induction of Bcl-x(S) expression in granulocytes through antisense oligonucleotide-mediated redirection of bcl-x pre-mRNA splicing were sufficient to induce significant apoptosis in these cells. Taken together, these results reveal that basal NF-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes through regulation of distinct members of the Bcl-2 family. This study sheds light on the constitutive mechanisms by which NF-kappaB maintains defense integrity.
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PMID:Constitutive nuclear factor-kappaB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the expression of distinct Bcl-2 family proteins. 1198 24

The purpose of this study was to evaluate the distribution and frequency of apoptosis-related proteins and their correlation with estrogen, progesterone, and androgen receptors in endometrial tissues. Immunohistochemical analyses of bcl-2, bax, bcl-x, and steroid receptors were performed in 22 endometrial carcinomas, 26 endometrial hyperplasias, and 19 cases of normal cyclical endometrium. Bcl-2 was expressed in 45.4% of carcinomas and 92.3% of hyperplasias. Bax immunostaining was found in 90.9% of carcinomas and 76.9% of hyperplasias. Bcl-x positivity was similar in carcinomas (68.1%) and endometrial hyperplasias (76.9%). In normal cyclical endometria, bcl-2 staining was intense and diffuse in the proliferative phase, but decreased dramatically in the early and mid-secretory phase to reappear in the late secretory phase. Bax was expressed throughout the menstrual cycle but more strongly in the secretory phase. Bcl-x displayed a similar degree of expression in proliferative and secretory endometria. Nineteen carcinomas (86.3%), 25 hyperplasias (96.1%), and 18 normal cyclical endometria (94.7%) were positive for estrogen receptor (ER). Progesterone receptor (PR) was observed in 20 carcinomas (90.9%), all hyperplasias (100%), and 18 normal cyclical endometria (94.7%). Androgen receptor (AR) positivity was seen in 7 carcinomas (31.8%), 6 hyperplasias (23.0%), and 3 normal cyclical endometria (15.7%). There was a statistically positive correlation between bcl-x and ER and a tendency toward significant correlation between bcl-x and PR and between ER and PR in carcinomas. In hyperplasias, there was a significant positive correlation between bcl-2 and PR and between bcl-2 and bax and a negative correlation between ER and bax. There was a statistically significant difference for bcl-2 (p = 0.001) and bax (p = 0.001) between the hyperplasia and carcinoma groups. There was increased expression of bax, decreased expression of bcl-2, and persistence of bcl-x protein in advanced endometrial carcinomas. Our findings show that ovarian hormones have a regulatory role on bcl-2 protein and that there is a correlation between other members of the bcl-2 family (bcl-x and bax) and steroid hormone receptors. Bax/bcl-x may be the major control mechanisms of apoptosis in advanced carcinomas; other members of the bcl-2 family may also be under hormonal control.
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PMID:Apoptosis-related proteins and steroid hormone receptors in normal, hyperplastic, and neoplastic endometrium. 1235 86

Aberrant expression of bcl-gene products has been implicated in the development of non-melanoma skin cancers. Recently, altered expression of alpha-smooth muscle actin has been proposed as predictive of tumour behaviour in basal cell carcinomas. The purpose of this study was to compare the aggressive and non-aggressive basal cell carcinomas in terms of bcl-gene products and alpha-smooth muscle actin expression. Fifty excisional biopsy samples were studied by immunohistochemical technique for the differential expressions of bcl-2, bax, bcl-x and alpha-smooth muscle actin. Bcl-2, bcl-x and bax were expressed in 34 (68%), 38 (76%) and 41(82%) specimens, respectively. Immunoreactivity for alpha-smooth muscle actin was noted both in tumour nests (64%) and within the stroma (54%). There was a significant difference between aggressive and non-aggressive basal cell carcinomas in terms of bcl-2 and stromal alpha-smooth muscle actin immunoreactivity. Non-aggressive basal cell carcinomas display a concordant expression of bcl-family proteins, whereas aggressive tumours reveal a discordant pattern. An increased expression of stromal alpha-smooth muscle actin with a concomitant decrease or loss of bcl-2 expression may be highly suggestive of aggressiveness in basal cell carcinoma.
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PMID:Bcl-2-related proteins, alpha-smooth muscle actin and amyloid deposits in aggressive and non-aggressive basal cell carcinomas. 1257 47

Esophageal adenocarcinoma arising on a background of Barrett's esophagus is increasing in incidence. A molecular understanding of both the progression of Barrett's esophagus and the factors determining the response of adenocarcinoma to neoadjuvant therapy is required, and this study focused on the role of proteins regulated by the bcl-2 family of genes, which are important regulators of programmed cell death (apoptosis). In total, 48 patients (36 men, 12 women) with Barrett's adenocarcinoma were studied. All patients received preoperative chemoradiotherapy followed by surgery. Bcl-2, bax and bcl-x protein expression were detected by standard avidin-biotin peroxidase method. Bcl-2, bax and bcl-x expression were detected in 84%, 80%, and 76%, respectively, of normal squamous mucosa. An increasing degree of dysplasia in Barrett's mucosa both before and after chemoradiotherapy was significantly associated with a reduction of bcl-2 expression (P = 0.03 and 0.009, respectively). Bcl-2 expression was significantly associated with tumor differentiation (P = 0.03) and a trend towards earlier T stage (P = 0.08), but not with nodal status. Pre-therapeutic bcl-2, bax and bcl-x protein expression (27%, 75%, and 87.5%, respectively) were not associated with tumor response or resistance to therapy. Bcl-2-positive patients had a significantly improved survival compared with bcl-2-negative tumors. A significant reduction of bcl-2 expression is associated with the progression of Barrett's mucosa to adenocarcinoma. Bcl-2 expression was associated with improved survival. Preoperative chemoradiotherapy induces expression of bax and bcl-x protein. The pretreatment expression of bcl-2 and related proteins did not predict response or resistance to neoadjuvant chemoradiotherapy, suggesting that regulators of apoptosis alone do not determine the response of Barrett's adenocarcinoma to neoadjuvant therapy.
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PMID:Loss of Bcl-2 expression in Barrett's dysplasia and adenocarcinoma is associated with tumor progression and worse survival but not with response to neoadjuvant chemoradiation. 1258 Dec 49

Prolactin (PRL)-dependent rat pre-T Nb2 (Nb2-11) cell lines serve as a useful model for investigation of mechanisms underlying lactogen-mediated suppression of apoptosis. Glucocorticoids, such as dexamethasone (DEX), induce apoptosis in Nb2-11 cells; the addition of PRL abrogates the cytolytic actions of DEX in this model, presumably because of increased expression of survival genes. In the present study, we investigated whether inhibition of DEX-induced apoptosis by PRL in Nb2-T cells was accompanied by altered expression of Bcl-2 family members, mcl-1, bad or bcl-x(L) determined by Northern and immunoblot analysis. The results indicated that a 0.9 kb bcl-x(L) transcript was rapidly induced by PRL. It reached maximal levels within 2 to 4 h (>20-fold) before declining toward basal values. Similar results were obtained in primary cultures of mouse thymocytes exposed to DEX in combination with PRL. In addition to increasing its mRNA expression, PRL also increased Bcl-xL protein levels by 6 h. Moreover, the effect of PRL to increase bcl-x(L) appeared to reflect direct and indirect mechanisms, since it was attenuated by the inhibition of protein synthesis. Results from other experiments suggest that PRL signaling to bcl-x(L) expression was independent of the Jak2/Stat pathway but appeared to require activation of a Src tyrosine kinase. In contrast, while a 1.1 kb mcl-1 transcript was detected in proliferating and quiescent cells, PRL did not alter its expression at either mRNA or protein levels. Moreover, neither bad mRNA nor its protein product were detectable under any of the experimental conditions evaluated. We have concluded that bad and mcl-1 are unlikely candidates for apoptosis regulatory genes modulated by PRL. However, the kinetic pattern of PRL-provoked bcl-x(L) expression is consistent with its playing a role as an apoptosis suppressor in Nb2-T cells and primary cultures of mouse thymocytes exposed to glucocorticoids.
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PMID:Prolactin regulation of Bcl-2 family members: increased expression of bcl-xL but not mcl-1 or bad in Nb2-T cells. 1290 74


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