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)

All-trans retinoic acid (ATRA) is able to specifically differentiate acute promyelocytic leukemic cells (APL) in short-term culture. Patients with APL achieved complete remission within 1-3 months by a progressive maturation of leukemic cells. The advantages of this differentiation therapy are the rapid disappearance of the bleeding disorders and the absence of aplastic phase avoiding the early deaths occurring in 15-30% of patients with conventional chemotherapy. However, relapses occurred when ATRA alone was maintained. For this reason, a chemotherapy is added after complete remission obtained by ATRA. A pilot study on 27 patients was proposed with the sequential combination of ATRA and chemotherapy. A European trial randomizes conventional therapy to the sequential ATRA-chemotherapy protocol. Retinoic acid receptor (RAR alpha) is rearranged by the specific translocation t(15;17) of APL; a PCR technique was developed in order to ensure the diagnosis and to follow the minimal residual disease. Transfection experiment of the chimaeric gene inhibits the transactivation of the natural RAR. ATRA is able to revert the arrest of maturation perhaps through an increase of the expression of the normal allele of RAR, which could overpass the impairment induced by the chimaeric protein on target responsive elements. One of the steps of the repair is the modulation of programmed cell death (PCD). Bcl-2, a gene involved in the PCD, is modulated in in vitro studies, arguing for the engagement of the cell in the natural death. The beneficial effect of differentiation therapy is probably due to the induction of the natural death of the malignant cell.
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PMID:All-trans retinoic acid (ATRA) therapeutical effect in acute promyelocytic leukemia. 146 48

Retinoic acid and hydrocortisone (HC) have been shown to regulate the drug sensitivity of the blast cells of acute myeloblastic leukemia (AML). We asked if the proto-oncogene bcl-2 played a role in this regulation. As target cells we used the continuous lines, OCI/AML-1, OCI/AML-2 or OCI/AML-5; expression of bcl-2 can be detected by Northern analysis of RNA from OCI/AML-2 or OCI/AML-5 cells; bcl-2 expression can be found in OCI/AML-1 cells only by using RT-PCR. Exposure of OCI/AML-2 or OCI/AML-5 cells to retinoic acid (all-trans retinoic acid, ATRA) led to a down-regulation of bcl-2 expression that was first seen after 2 h of exposure and was complete after a day. The down-regulation could be prevented by exposing the cells to ara-C either before or after ATRA; decrease in bcl-2 protein was moderate and only obvious after 36 h of ATRA treatment. Nuclear run-on experiments provided evidence that bcl-2 down-regulation was occurring at transcriptional and post-translational levels. Since bcl-2 is considered to have anti-oxidant activity, we tested the sensitivity of the three cell lines to H2O2; we found that OCI/AML-1, the line with very low bcl-2 expression, was a 100-fold more H2O2-sensitive than OCI/AML-2 or OCI/AML-5, where bcl-2 expression can be detected readily. We then asked if H2O2 sensitivity could be regulated. We found that exposure of cells to HC before H2O2 was protective while ATRA after peroxide treatment increased killing; this is the same pattern of regulation observed when AML blasts are exposed to HC before, or ATRA after ara-C. Finally, we asked whether N-acetylcysteine (NAC), a known radical scavenger would protect cells against ara-C killing. Significant protection was observed when NAC was given before drug, but not if given after drug. NAC protection against ara-C killing was seen for OCI/AML-1 and 2 cells, but not for OCI/AML-5 cells. We interpret the results as follows: ara-C kills cells in two ways: first, directly, by incorporation into DNA and chain termination; second, indirectly, by inducing the production of toxic radicals. Bcl-2 reduces the oxidant activity of such radicals, and is protective. ATRA regulates ara-C toxicity by its action on bcl-2. Left unexplained are the action of HC, which does not affect bcl-2 expression and the mechanism by which ara-C prevents down-regulation of bcl-2 by ATRA.
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PMID:Mechanism of cytosine arabinoside toxicity to the blast cells of acute myeloblastic leukemia: involvement of free radicals. 776 41

Human catecholaminergic neuroblastoma cells (SH-SY5Y) have been widely used in different neurochemical investigations. Quite often these cells are induced to differentiation by various agents, such as staurosporine and retinoic acid. Interestingly, even though both staurosporine and retinoic acid induce similar morphological differentiation in SH-SY5Y cells, we found that these two groups of differentiated cells exhibited opposite vulnerability to harmful chemicals and physical insults. In the present study, cisplatin, 5-fluorouracil (5-FU), N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), 6-hydroxydopamine (6-OHDA), and gamma-radiation were used to assess the tolerance of the differentiated cells. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Staurosporine-treated SH-SY5Y cells were more sensitive to these toxic insults than the untreated controls. In contrast, retinoic acid-treated cells became more resistant to the same treatments. The expression of the proteins of the protooncogene Bcl-2 and the tumor suppressor gene p53 following staurosporine or retinoic acid treatment was assessed by Western blot and immunocytochemistry. Retinoic acid increased Bcl-2 and decreased p53 levels, whereas staurosporine decreased Bcl-2 and increased p53 levels. The opposite alteration of Bcl-2 (anti-apoptotic) and p53 (apoptotic) contents in SH-SY5Y cells with retinoic acid and staurosporine are attributed to the changes in cell vulnerability. These observations also indicate that caution should be taken when chemically induced differentiated neuroblastoma cells are to be used as an in vitro model for studying neuronal survival.
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PMID:Differential effects of staurosporine and retinoic acid on the vulnerability of the SH-SY5Y neuroblastoma cells: involvement of bcl-2 and p53 proteins. 1051 16

Differentiation and apoptosis are precisely regulated events in early embryogenesis. Retinoic acid-induced differentiation in the embryonal carcinoma (EC) cell line NCR-G3 triggers concurrent induction of apoptosis. Using this system, which serves as a model of early embryogenesis, the expression of various bcl-2-related genes was analyzed as these genes display either positive or negative regulatory effects on apoptosis. EAT/mcl-1, an antiapoptotic bcl-2-related gene and immediate early gene, was dramatically expressed at an early stage of NCR-G3 differentiation. Bcl-xL, another antiapoptotic gene, was induced at a middle stage of differentiation and then gradually decreased to basal level. Expression of Bax, a proapoptotic molecule, was detected at a high level and remained relatively constant. Meanwhile, Bcl-2 and Bcl-xS were below detectable levels throughout the various stages of differentiation. As the balance of bcl-2 genes is a crucial regulatory step in apoptosis, the results suggest that EAT and Bax likely regulate apoptosis in the early stages of differentiation. In later stages of differentiation, down-regulation of EAT was found to coincide with a gradual increase in apoptosis of NCR-G3 cells. Furthermore, use of the monoclonal antibody (3A2) specific to EAT revealed that EAT is localized to the outer mitochondrial membrane in human EC cells. In addition, EAT immunoreactivity was not detected in apoptotic NCR-G3 cells while it was observed in nearly all viable cells. The findings suggest that rapid induction of EAT may prevent NCR-G3 cells from undergoing apoptosis, thereby supporting viability at the early stage of differentiation.
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PMID:EAT/mcl-1 expression in the human embryonal carcinoma cells undergoing differentiation or apoptosis. 1133 30

All-trans retinoic acid inhibits growth associated with downregulation of cyclin D1 and can cause low level apoptosis in estrogen receptor positive breast cancer cell lines. The cyclin D1 gene is amplified and/or the protein overexpressed in about one-third of breast cancers. Constitutive expression of cyclin D1 in estrogen receptor positive MCF-7 and ZR-75 breast cancer cells (MCF-7(cycD1) and ZR-75(cycD1)) Increased the fraction of cells in S phase and reduced the G1 accumulation following retinoic acid treatment compared with control cells. However, culture of MCF-7(cycD1) with 1 microM all-trans retinoic acid resulted in about threefold greater growth inhibition compared with vector-transfected cells. Hoechst staining of DNA and in situ DNA end-labeling analysis indicated that MCF-7(cycD1) and ZR-75(cycD1) cultures contained 4-6-fold more retinoic acid-induced apoptotic nuclei as vector-transfected cells. Retinoic acid treatment of vector-transfected clones resulted in Bax protein activation as assessed by exposure of the NH(2)-terminus of Bax but the proportion of cells containing activated Bax was increased in cyclin D-expressing cells treated with retinoic acid. The latter cells also displayed both immunocytochemical and biochemical evidence of translocation of cytochrome c into the cytosol following RA-treatment. Retinoic acid markedly decreased the Bcl-2 levels in MCF-7 and ZR-75 cells. Accordingly, coexpression of Bcl-2 and cyclin D1 rendered the cells resistant to retinoic acid-induced apoptosis. We conclude that constitutive expression of cyclin D1 sensitizes ER-positive breast cancer cells to a retinoic acid-induced mitochondrial death pathway involving Bax activation, cytochrome c release and caspase-9 cleavage.
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PMID:Ectopic expression of cyclin D1 amplifies a retinoic acid-induced mitochondrial death pathway in breast cancer cells. 1142 97

Retinoic acid (RA), the most biologically active metabolite of vitamin A, is known to modulate cell proliferation, apoptosis and differentiation, with different effects depending on the cellular context. Retinoic acid can exert its effects by directly or indirectly influencing the expression of genes involved in the control of cell proliferation. In the present report we investigate the possible correlation between the antiproliferative, differentiative and apoptotic effects previously observed on rat hepatocytes and HepG2 cells, with a possible modulation of cell-cycle regulators. We demonstrate that RA induces growth arrest and differentiation in HepG2 cells by influencing the activities of cyclin-cdk complexes involved in the regulation of G1/S transition and S-phase progression, in particular by modifying the binding of these complexes to p21 and p27 inhibitors. In fetal cells, however, the induction of apoptosis and differentiation by RA was obtained via inhibition of cyclin D1-cdk4 activity, as result of an increased binding to the p16 inhibitor. Retinoic acid also modulates c-myc and Bcl-2 expression. In conclusion, our data suggest that RA could be useful to regulate the reversion of transformed phenotype and could also be utilized as a chemiopreventive agent in cells of hepatic origin.
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PMID:Retinoic acid modulates the cell-cycle in fetal rat hepatocytes and HepG2 cells by regulating cyclin-cdk activities. 1295 81

Retinoic acid and transforming growth factor-beta (TGF-beta) affect differentiation, proliferation and carcinogenesis of epithelial cells. The effect of both compounds on the proliferation of cells of the hormone sensitive human breast cancer cell line (ER+) MCF-7 was assessed in the presence of estradiol and tamoxifen. The assay was based on [3H]thymidine incorporation and the proliferative activity of PCNA- and Ki 67-positive cells. The apoptotic index and expression of the Bcl-2 and p53 antigens in MCF-7 cells were also determined. Exogenous TGF-beta1 added to the cell culture showed antiproliferative activity within the concentration range of 0.003-30 ng/ml. Irrespective of TGF-beta1 concentrations, a marked reduction in the stimulatory action of estradiol (10(-9) and 10(-8) M) was observed whereas in combination with tamoxifen (10(-7) and 10(-6) M) only 30 ng/ml TGF-beta1 caused a statistically significant reduction to approximately 30% of the proliferative cells. In further experiments we examined the effect of exposure of breast cancer cells to retinoids in combination with TGF-beta1. The incorporation of [3H]thymidine into MCF-7 cells was inhibited to 52 +/- 19% (control =100%) by 3 ng/ml TGF-beta1, and this dose was used throughout. It was found that addition of TGF-beta1 and isotretinoin to the culture did not decrease proliferation, while TGF-beta1 and tretinoin at low concentrations (3 x 10(-8) and 3 x 10(-7) M) reduced the percentage of proliferating cells by approximately 30% (67+/-8% and 67+/-5%, P<0.05 compared to values in the tretinoin group). Both retinoids also led to a statistically significant decrease in the stimulatory effect of 10(-9) M estradiol, attenuated by TGF-beta1. In addition, the retinoids in combination with TGF-beta1 and tamoxifen (10(-6) M) caused a further reduction in the percentage of proliferating cells. Immunocytochemical analysis showed that all the examined compounds gave a statistically significant reduction in the percentage of cells with a positive reaction to PCNA and Ki 67 antigen. TGF-beta1, isotretinoin and tretinoin added to the culture resulted in the lowest percentage of PCNA positive cells. However, the lowest fraction of Ki 67 positive cells was observed after addition of isotretinoin. The obtained results also confirm the fact that the well-known regulatory proteins Bcl-2 and p53 play an important role in the regulation of apoptosis in the MCF-7 cell line, with lowered Bcl-2 expression accompanying easier apoptotic induction. The majority of the examined compounds act via the p53 pathway although some bypass this important proapoptotic factor.
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PMID:Can transforming growth factor-beta1 and retinoids modify the activity of estradiol and antiestrogens in MCF-7 breast cancer cells?. 1544 35

Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LA-N-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.
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PMID:Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma. 1656 81

Human papillomavirus (HPV) infection is believed to be the central cause of cervical cancer. The viral proteins E6 and E7 from high-risk HPV types prevent cells from differentiating apoptosis and inducing hyperproliferative lesions. Human cervical carcinoma HeLa cells contain integrated human papillomavirus type 18 (HPV-18). Retinoic acid (RA) is a key regulator of epithelial cell differentiation and a growth inhibitor in vitro of HeLa cervical carcinoma cells. Cellular responses to RA are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors. On the other hand, histone deacetylase inhibitors have been shown to be chemopreventive agents for the treatment of cancer cells. In this article, we have examined the antiproliferative effect of RA and histone deacetylase inhibitor BML-210 on HeLa cells, and particularly the effects on protein expression that may be involved in the cell cycle control and apoptosis. Our data suggest that a combination of RA and BML-210 leads to cell growth inhibition with subsequent apoptosis in a treatment time-dependent manner. We confirm that BML-210 alone or in combination with RA causes a marked increase in the level of p21. The changes in the p53 level are under the influence of p38 phosphorylation. We also discovered that the histone deacetylase inhibitor BML-210 causes increased levels of anti-apoptotic protein Bcl-2 and phosphorylated p38 MAP Kinase; the latter link in cell cycle arrest with response to extracellular stimuli. Our results suggest that RA and BML-210 are involved in different signaling pathways that regulate cell cycle arrest and lead to apoptosis of HeLa cells.
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PMID:Retinoic acid and histone deacetylase inhibitor BML-210 inhibit proliferation of human cervical cancer HeLa cells. 1734 27

Retinoic acid (RA), similar to specific growth factors, can induce differentiation of proliferating promyelocytic precursors into terminally differentiated granulocytes, although little is known about effects of its 13-cis isomer on promyelocytic leukemia (PML). In this study we demonstrate that 13-cis-RA has a dose and time-dependent antiproliferative effect on HL-60 PML cell line, that it induces cell accumulation in resting G0/G1 phase of the cell cycle followed by an increase in CD11b granulocyte differentiation antigen expression. The obtained increase in the percentage of HL-60 cells in G0/G1 phase and complementary decrease in S phase of the cell cycle are accompanied by a decrease in the expression of cell cycle regulatory molecule cyclin B1. We also show the induction of interferon regulatory factor-1 (IRF-1) transcription that can, also, to some extent contribute to the antiproliferative effect of 13-cis-RA. Furthermore, down-regulation of Bcl-2 protein expression in 13-cis-RA treated HL-60 cells may contribute to sensitivity to apoptosis of growth arrested HL-60 promyelocytic cells.
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PMID:Antiproliferative effect of 13-cis-retinoic acid is associated with granulocyte differentiation and decrease in cyclin B1 and Bcl-2 protein levels in G0/G1 arrested HL-60 cells. 2008 80

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