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)

Exposure of organotypic rat corticostriatal slice cultures to the mitochondrial toxin 3-nitropropionic acid (3-NP) resulted in concentration-dependent loss of cresylviolet-stained cells and increase of lactate dehydrogenase and lactate efflux into the culture medium, indicators for cell death and metabolic activity in the slices, respectively. The involvement of apoptosis in these slices was suggested by using the terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL) technique, and immunohistochemistry for the apoptosis-related markers Bax and Bcl-2. In 3-NP-exposed slices, TUNEL-positive cells were observed in both the striatum and the cortex but in different forms: striatal neurons were either diffusely stained or showed nuclear fragmentation, cortical neurons only exhibiting nuclear fragmentation. In 3-NP-exposed slices, the pro-apoptotic protein Bax was abundantly expressed, whereas the anti-apoptotic protein Bcl-2 was not expressed in striatal neurons. We suggest that both apoptosis and necrosis are involved in the 3-NP-treated slices, apoptosis as well as necrosis in the striatum and apoptosis in the cortex.
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PMID:3-Nitropropionic acid induces cell death and mitochondrial dysfunction in rat corticostriatal slice cultures. 1216 Dec 69

This study investigated the influence of chronic hyperthyroidism on mammary function in lactating rats and the effects on their pups. Thyroxine-treated (10 microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats were mated 2 weeks after the start of treatment and killed with their litters on days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3)) and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers, serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like growth factor I (IGF-I) and progesterone concentrations decreased, and corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14 of lactation, and growth hormone increased on day 7 of lactation. Mammary prolactin binding sites did not vary, but there was an increase in the binding sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute suckling experiment, thyroxine-treated rats released less oxytocin, growth hormone and prolactin and excreted less milk than did control rats. Mammary casein, lactose and total lipid concentrations in thyroxine-treated rats were similar to those of control rats on day 14 of lactation. Histological studies of the mammary glands showed an increased proportion of alveoli showing reduced or no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats. Expression of SGP-2, a gene expressed during mammary involution, increased in thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of insulin-like growth factor binding protein 5, a proapoptotic signal, was unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was unchanged, whereas expression of IGF-I, which also promotes survival of mammary gland epithelial cells, increased on day 21 of lactation in thyroxine-treated rats. These results indicate that thyroxine treatment produces some milk stasis as a result of impairments in suckling induced release of oxytocin that may initiate the first stage of mammary involution, increasing apoptosis in a gland that is otherwise actively producing and secreting milk.
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PMID:Hyperthyroidism and production of precocious involution in the mammary glands of lactating rats. 1241 8

Naturally occurring cell death has been extensively analyzed in many tissues, but little data exist regarding its occurrence in developing skeletal muscle. We investigated its occurrence and time course in rat hindlimb skeletal muscles during the first 3 weeks of postnatal development, its morphological and biochemical features, and the concomitant expression of Bax, Bcl-2, and Bcl-x(L). Myofibers displaying morphological features of apoptosis were found during the first 9 postnatal days. Terminal transferase (TdT)-mediated dUTP-biotinylated nick end labeling (TUNEL)-positive nuclei were present at all days examined and peaked between postnatal days 5 and 7. Total genomic DNA extracted from muscles at postnatal days 5, 7, and 9 showed internucleosomal fragmentation after Southern hybridization. Constitutive levels of Bax, Bcl-2, and Bcl-x(L) were detected by means of reverse transcriptase-polymerase chain reaction (RT-PCR) analysis at all ages examined, with a moderate increase around the period of maximal apoptosis. The results show that apoptosis and a concurrent expression of some genes of the Bcl-2 family, occur postnatally in rat skeletal muscle. This information is relevant to studies addressing the mechanisms of developmental muscle injuries.
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PMID:Naturally occurring cell death during postnatal development of rat skeletal muscle. 1245 1

Phenylacetate is a differentiation agent and has anticancer activity with relatively low toxicity. In the present study, we examined the anticancer effect of six synthetic phenylacetate derivatives in human lung cancer cells in our search for more effective phenylacetate analogous. Results showed that the antiproliferative effects of these synthetic compounds were stronger than those of phenylacetate, and that N-butyl-2-(2-fluorolphenyl)acetamide (SCK6) is the most potent compound. To address the mechanism of the antiproliferative effect of SCK6, cell cycle analysis was performed. Result showed that SCK6 (1 mM) induced G(1) arrest in CH27 cells. Western blot analysis of G(1) phase regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase 2 (Cdk2), Cdk4, Cyclin E and Cyclin D3 were decreased after treatment with SCK6 but not those of Cdk6, Cyclin D1 and D2. In contrast, SCK6 increased the protein levels of p53 and p21(CIP1/WAF1). Data from in situ terminal transferase-mediated dUTP-fluorescensin nick end-labeling (TUNEL) assay and DNA fragmentation analysis demonstrated that SCK6 induced apoptotic cell death in CH27 cells. This SCK6-induced apoptosis was accompanied by a downregulation of Bcl-2 protein and activation of the caspase-9 cascade. Overexpression of Bcl-2 by adeno-Bcl-2 vector infection significantly inhibited SCK6-induced apoptosis. Moreover, treatment with caspase inhibitors also markedly reduced cell death induced by SCK6. Taken together, these results suggest that downregulation of G(1)-associated Cdks and cyclins and upregulation of p53 and p21(CIP1/WAF1) may contribute to SCK6-mediated G(1)-phase arrest. Furthermore, the decrease in Bcl-2 and the activation of caspase-9/caspase-3 may be the effector mechanism through which SCK6 induces apoptosis.
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PMID:A phenylacetate derivative, SCK6, inhibits cell proliferation via G1 cell cycle arrest and apoptosis. 1270 52

Bcl-2 is up-regulated by EBV in immortalized lymphoblastoid B cells and is expressed in the majority of EBV-associated lymphoproliferative diseases, including posttransplant lymphoproliferative disorder (PTLD) and AIDS-related lymphoma (ARL). Given the antiapoptotic and chemoprotective effect of Bcl-2, it represents a logical target for modulation using antisense strategies in PTLD and ARL. We previously examined the antitumor effects of a fully phosphorothioated Bcl-2 antisense oligonucleotide, G3139, in EBV(+) lymphoproliferative disease in vitro and in vivo using the human/severe combined immunodeficient (SCID) chimeric model of PTLD. These studies showed that G3139 treatment decreased Bcl-2 protein levels in association with antiproliferative and proapoptotic effects in lymphoblastoid cell lines (LCLs) in vitro. In vivo, although G3139 treatment completely abrogated EBV(+) lymphoid tumor engraftment in the human/SCID model of PTLD, antisense treatment alone was not curative in animals with established tumors. Because the humanized anti-CD20 antibody, rituximab, has antitumor activity in patients with PTLD and stimulates apoptosis in some lymphoid cell lines, we sought to determine whether Bcl-2 antisense treatment potentiates the antitumor effects of rituximab in EBV-associated lymphoproliferative disease in vitro and in vivo. Proliferation assays by thymidine uptake in LCLs showed that G3139 but not control oligonucleotides augmented the antiproliferative effect of rituximab. Flow cytometric terminal deoxynucleotidyltransferase-mediated nick end labeling assays confirmed that G3139 treatment enhanced the apoptotic response of LCLs to rituximab, and this interaction was oligonucleotide sequence dependent. To test the in vivo efficacy of G3139 and rituximab in the human/SCID model of PTLD, we used a delayed treatment schedule that permitted detection of enhanced antitumor activity of combination therapy. Although G3139 or rituximab treatment significantly prolonged survival compared with untreated controls, 89% of animals in the monotherapy arms died with disseminated tumors. In contrast, 79% of animals in the combined G3139 and rituximab arm remained tumor free for the duration of follow-up (>160 days) with no evidence of tumors at the time of sacrifice, indicating that G3139 in combination with rituximab was curative therapy in the majority of tumor-bearing animals. These studies demonstrated that G3139 potentiates the antitumor response of PTLD to rituximab in vivo and augments the antiproliferative and apoptotic effects of rituximab in vitro in LCLs. This is the first report of G3139 potentiating the antitumor activity of an antibody-based therapy both in vitro and in vivo. Bcl-2 antisense oligonucleotide therapy in combination with rituximab may represent a promising nontoxic and effective targeted therapy for EBV-associated lymphoproliferative diseases such as PTLD and ARL. Furthermore, this approach may have broader applications to other Bcl-2- and CD20-expressing lymphoid malignancies.
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PMID:Bcl-2 antisense (G3139, Genasense) enhances the in vitro and in vivo response of Epstein-Barr virus-associated lymphoproliferative disease to rituximab. 1273 52

The biological behavior of hepatocellular carcinoma (HCC) is, in part, relevant to apoptosis. A systematic investigation of the apoptosis-related Bcl-2 family modulated by p53 in HCC is lacking. A total of 22 HCC patients were studied. The expression of p53 protein in HCC was assessed using the immunohistochemical method, which categorized the HCC patients into two groups: group 1, with immunonegative p53 (N = 7); and group 2, with immunopositive p53 (N = 15). The expression of p53, p21, Bcl-2, Bax, Bcl-xL, and Bcl-xS in the 22 HCC cases detected by western bioting was quantified with a densitometer. The apoptosis of the 22 HCC cases was determined by terminal deoxynucleotidyltransferase-mediated UTP end-labeling (TUNEL). We found that Bcl-2 was remarkably up-regulated in group 2 (14 of 15), but was down-regulated in group 1 (5 of 7). Bax was up-regulated in both group 1 (6 of 7) and group 2 (13 of 15). Bcl-xL was up-regulated in both group 1 (5 of 7) and group 2 (9 of 15). Bcl-xS was remarkably down-regulated in group 2 (14 of 15) compared to group 1 (4 of 7). The apoptosis indexes of groups 1 and 2 were 0.82 +/- 0.26% and 0.33 +/- 0.17%, respectively (P = 0.023). The long-term survival of group 1 was superior to that of group 2 (log-rank test, P = 0.001). In conclusion, Bcl-2 and Bcl-xS represented the most significant anti- and proapoptotic proteins, respectively, modulated through a p53-dependent pathway in HCC.
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PMID:Expression of Bcl-2 family modulated through p53-dependent pathway in human hepatocellular carcinoma. 1274 54

The active vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) and related substances have previously been tested in tissue culture and animal models of retinoblastoma for their use as anti-tumor drugs. However, despite of the potential therapeutic value, the molecular mechanisms through which 1,25-(OH)(2)D(3) inhibits the growth of retinoblastoma cells are incompletely understood. To elucidate possible signalling pathways for the anti-proliferative action of vitamin D compounds in retinal tumor cells, we analyzed the effect of 1,25-(OH)(2)D(3) and its synthetic analogue KH1060 on the growth of human retinoblastoma-derived Y79 cells. Vitamin D receptor (VDR) mRNA was detected by reverse transcription PCR in Y79 cells and in tissue specimens of human retinoblastoma. VDR transcripts were confirmed at the protein level by strong immunostaining of solid retinal tumors for VDR. Incubation with 1,25-(OH)(2)D(3) and KH1060 (10(-10)-10(-6)moll(-1)) decreased the number of Y79 cells in a timely and dose-dependent manner. Treatment with 1,25-(OH)(2)D(3) (10(-10)moll(-1)) for 24 hr caused cell cycle arrest in the G0/1 phase. Apoptosis of Y79 cells in response to 1,25-(OH)(2)D(3) was demonstrated by the means of TdT-dUTP terminal nick-end labelling (TUNEL), annexin V staining, and detection of DNA fragmentation on agarose gels. 1,25-(OH)(2)D(3)-induced programmed death of Y79 cells was accompanied by a concentration-dependent increase in Bax protein and a reduction in Bcl-2 content. These findings suggest that 1,25-(OH)(2)D(3) inhibits the growth of retinoblastoma cells by causing cell cycle arrest and apoptosis. 1,25-(OH)(2)D(3)-induced programmed death of retinoblastoma cells appears to involve reciprocal changes in Bcl-2 and Bax proteins.
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PMID:1,25-dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. 1282 82

Kainic acid induces excitotoxicity and nerve cell degeneration in vulnerable regions of rat brain, most markedly in hippocampus and amygdala. Part of the cell death following kainic acid is apoptotic as shown by caspase 3 activation and chromatin condensation. Here we have studied the regulation of pro- and anti-apoptotic proteins belonging to the Bcl-2 family in rat hippocampus and amygdala by kainic acid in relationship to ensuing neuronal death. The pro-apoptotic protein Bax was up-regulated in hippocampus 6 h after kainic acid administration. The increase in Bax was followed by the appearance of TdT-mediated dUTP nick end labelling-positive cells which were prominent at 24 h. Immunohistochemistry for active Bax revealed a punctuated labelling of neurons in the CA3 and hilar regions of hippocampus as well as in amygdala. Double staining for NeuN, a marker for nerve cells, and TdT-mediated dUTP nick end labelling showed that mainly neurons undergo degeneration after kainic acid treatment. In contrast to Bax, the pro-apoptotic BH3-only Bcl-2 proteins Bim and Harakiri/DP5 were down-regulated by kainic acid. This was also observed for the anti-apoptotic proteins Bcl-x and Bcl-w. Immunoreactive Bcl-2 was up-regulated in hippocampus after kainic acid together with an increase in the phosphorylation of serine-87 in Bcl-2, suggesting a post-transcriptional modification of the protein. This was confirmed using immunoprecipitation of total Bcl-2 from hippocampus and amygdala which revealed an increase in serine-87 phospho-Bcl-2 after kainic acid. Inhibition of the c-jun N-terminal protein kinase pathway reduced both serine-87 phosphorylation and cell death after kainic acid. This indicates an important role of Bcl-2 phosphorylation in controlling neuronal death after kainic acid. In contrast to the situation in trophic factor-deprived neurons, no up-regulation of Bim or Harakiri/DP5 proteins occurred after kainic acid, suggesting alternative pathways for regulation of cell death in excitotoxicity. The results indicate that not only the relative levels of Bcl-2 family proteins but also conformation changes and post-translational modifications contribute to neuronal death following kainic acid.
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PMID:Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. 1295 12

The majority of follicular lymphoma and Burkitt's lymphoma are associated with reciprocal translocations involving BCL2 and cMYC, respectively. Unusual reports of aggressive lymphoma presenting with both translocations have been described as well as rare cases with a third structural alteration usually involving BCL6. The patient described here presented with aggressive high-grade lymphocytic leukemia, FAB subtype L2 (ALL-L2), and three reciprocal translocations, t(14;18)(q32;q21), t(8;14)(q24.1;q32), and t(1;2) (q22-23;p13). Despite immature morphology the leukemic blasts had a mature B-cell phenotype; they were positive for surface immunoglobulin heavy chains and negative for CD34, TdT, and CD10. Most reported dual t(14;18)/t(8;14) cases have not shown sIg and were positive for CD10. Molecular genetic analyses showed the typical rearrangements of BCL2 and cMYC as well as the FCGR2B gene on chromosome 1q23. The occurrence of a third oncogene rearrangement in association with the dual BCL2, cMYC translocations in ALL patients is very rare. To our knowledge, this is the first case where the third hit involves the FCGR2B locus. This report reiterates the poor prognosis associated with activation of cMYC together with elevated Bcl-2 expression. These data also support recent evidence that dysregulation of FCGR2B may play a role in tumor progression.
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PMID:Case of acute lymphoblastic leukemia presenting with t(14;18)/BCL2, t(8;14)/cMYC, and t(1;2)/FCGR2B. 1450 97

An in vitro ischemia model was established and the effect of the metabolic inhibitors cycloheximide (CHX) and actinomycin D (ActD) on apoptosis in astrocytes under ischemia studied. CHX decreased by 75% the number of cells dying after 6 hr of ischemia compared with control cultures. TdT-mediated dUTP nick end labelling (TUNEL) staining of comparable cultures was reduced by 40%. ActD decreased cell death by 60% compared with controls. The number of TUNEL-positive cells was reduced by 38%. The nuclear shrinkage in TUNEL-positive astrocytes in control cultures did not occur in ActD-treated astrocytes, indicating that nuclear shrinkage and DNA fragmentation during apoptosis are two unrelated processes. Expression of bcl-2 (alpha and beta), bax, and Ice in astrocytes under similar ischemic conditions, as measured by quantitative reverse transcription-polymerase chain reaction, indicated that ischemia down-regulated bcl-2 (alpha and beta) and bax. Ice was initially down-regulated from 0 to 4 hr, before returning to control levels after 8 hr of ischemia. ActD decreased the expression of these genes. CHX reduced the expression of bcl-2 (alpha and beta) but increased bax and Ice expression. It is hypothesized that the balance of proapoptotic (Bad, Bax) and antiapoptotic (Bcl-2, Bcl-Xl) proteins determines apoptosis. The data suggest that the ratio of Bcl-2/Bad in astrocytes following ActD and CHX treatment does not decrease as much in untreated cells during ischemia. Our data indicate that it is the ratio of Bcl-2 family members that plays a critical role in determining ischemia-induced apoptosis. It is also important to note that ischemia-induced apoptosis involves the regulation of RNA and protein synthesis.
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PMID:Cycloheximide and actinomycin D delay death and affect bcl-2, bax, and Ice gene expression in astrocytes under in vitro ischemia. 1451 61

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