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 investigated the role of p53 and of the Bcl-2 family proteins in the apoptotic response of a panel of testicular tumour cell lines (NT2, NCCIT, S2 and 2102 EP). The p53 gene status and the capacity of the p53 protein to transactivate the p21/WAF/CIP gene were determined, and we examined the correlation between p53 status and the susceptibility to cisplatin-induced apoptosis. In contrast to wild-type p53-containing NT2 and 2102 EP cells, NCCIT (mutant p53) and S2 (no p53 protein) cells were shown to be p53-transactivation defective. However, NCCIT and S2 cells with non-functional p53 were readily triggered into apoptosis by cisplatin, whereas p53-transactivation competent 2102 EP cells failed to undergo cisplatin-induced apoptosis. The defective apoptotic pathway in 2102 EP cells was reflected by a 4-fold decreased sensitivity to cisplatin in the MTT assay. We further demonstrated that the p53-independent differential cisplatin sensitivity among the testicular germ cell tumour (TGCT) cell lines was not due to differences in cellular cisplatin accumulation or DNA platination. The pattern of endogenous expression levels of Bax, Bcl-2, Bcl-x and Bak, which was not modulated by cisplatin treatment, demonstrated that these Bcl-2 family proteins are not involved in drug-induced apoptosis in the TGCT cell lines. Our results suggest a lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in our panel of TGCT cell lines. We conclude that the cisplatin-induced apoptotic pathway in TGCT cell lines might be p53-independent and is probably not associated with differences in the Bcl-2/Bax rheostat.
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PMID:Lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines. 938 77

We examined the sensitivity for cisplatin-induced apoptosis in a panel of four testicular germ cell tumour (TGCT) cell lines and monitored the cellular expression of the apoptosis-related proteins p53, Bcl-2 and Bax. Three of four TGCT cell lines (NT2, NCCIT and S2) were hypersensitive for cisplatin-induced apoptosis, while the TGCT cell line 2102 EP appeared to be resistant for cisplatin-induced apoptosis, even at relatively high drug concentrations (12.5 microM). For all four cell lines, the induction of apoptosis by cisplatin correlated with drug sensitivity in the MTT assay. The differences in chemosensitivity and induction of apoptosis could not be attributed to differences in cellular platinum accumulation, DNA platination or platinum-DNA adduct removal. We next analysed the relationship between p53 status and cisplatin-induced up-regulation of p53, and the susceptibility to cisplatin-induced apoptosis. Wild-type p53 containing NT2 and 2102 EP cells showed p53 up-regulation upon drug treatment, and NCCIT (mutant p53) and S2 (no p53 protein) cells did not. Consistently, the increase in wild-type p53 protein in NT2 and 2102 EP cells led to an increase in mRNA level of the p53 downstream gene p21/WAF/CIP, whereas mutant p53-containing NCCIT cells and p53-non-expressing S2 cells could not transactivate this p53-responsive gene. As NT2, NCCIT and S2 were readily triggered into apoptosis, while 2102 EP cells failed to undergo cisplatin-induced apoptosis, our data suggest that the presence of wild-type and/or transactivation-competent p53 might not be an absolute prerequisite for efficient induction of apoptosis in TGCT cell lines. Also endogenous levels of Bcl-2 and Bax expression did not correlate with cisplatin-induced apoptosis. In addition, the endogenous Bcl-2 and Bax expression was not affected by cisplatin treatment. The present study suggests that, at least in our panel of TGCT cell lines, hypersensitivity for cisplatin-induced apoptosis might not be necessarily correlated with the presence of wild-type p53 and is probably not associated with Bcl-2 and Bax expression.
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PMID:Expression of p53, Bcl-2 and Bax in cisplatin-induced apoptosis in testicular germ cell tumour cell lines. 963 29

Tissues with the highest rates of proliferation typically exhibit the highest frequencies of apoptosis, but the mechanisms that coordinate these processes are largely unknown. The homeodomain protein Gax is down-regulated when quiescent cells are stimulated to proliferate, and constitutive Gax expression inhibits cell proliferation in a p21(WAF/CIP)-dependent manner. To understand how mitogen-induced proliferation influences the apoptotic process, we investigated the effects of deregulated Gax expression on cell viability. Forced Gax expression induced apoptosis in mitogen-activated cultures, but quiescent cultures were resistant to cell death. Though mitogen activation was required for apoptosis, neither the cdk inhibitor p21(WAF/CIP) nor the tumor suppressor p53 was required for Gax-induced cell death. Arrest in G1 or S phases of the cell cycle with chemical inhibitors also did not affect apoptosis, further suggesting that Gax-mediated cell death is independent of cell cycle activity. Forced Gax expression led to Bcl-2 down-regulation and Bax up-regulation in mitogen-activated, but not quiescent cultures. Mouse embryonic fibroblasts homozygous null for the Bax gene were refractive to Gax-induced apoptosis, demonstrating the functional significance of this regulation. These data suggest that the homeostatic balance between cell growth and death can be controlled by mitogen-dependent pathways that circumvent the cell cycle to alter Bcl-2 family protein expression.
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PMID:Bax-mediated cell death by the Gax homeoprotein requires mitogen activation but is independent of cell cycle activity. 964 28

Activation of PKC with 5 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 72 h in human U937 myeloid leukemia cells is associated with induction of adherence, followed by monocytic differentiation and G0/G1 cell cycle arrest. In this study, we demonstrate that in addition to these effects about 25% of U937 cells accumulated in an apoptotic subG1 phase after TPA treatment. The appearance of these apoptotic suspension cells was detectable throughout the time course of the culture and was independent of TPA concentrations between 0.5 and 500 nM. Experiments with cells synchronized by centrifugal elutriation revealed dominant susceptibility of G1-phase cells to TPA-mediated apoptosis. While adherent cells expressed differentiation markers including the integrin CD11c, this effect was less pronounced in the TPA-treated suspension fraction. Moreover, previous work has demonstrated cell cycle arrest in differentiating U937 cells. Accordingly, PKC activation by TPA treatment was associated with a significant expression of the cdk/cyclin inhibitor p21WAF/CIP/sdi-1 in the adherent population and subsequent G0/G1 cell cycle arrest. In contrast, suspension cells failed to induce significant levels of p21WAF/CIP/sdi-1 after TPA stimulation. Immunoblotting experiments demonstrated no difference in the expression of the pro-apoptotic factors Bax, Bad, and Bak in either control U937 and TPA-treated adherent or suspension cells, respectively. However, anti-apoptotic factors including Bcl-2, Bcl-xL, and Mcl-1 were significantly induced in the adherent population whereas no induction was detectable in the suspension cells. In this context, incubation with the caspase-3/caspase-7 specific tetrapeptide inhibitor DEVD prior to TPA treatment prevented an accumulation of cells in subG1, respectively, demonstrating an involvement of these caspases. Taken together, these data suggest that PKC activation can relay distinct signaling pathways such as induction of adherence coupled with monocytic differentiation and growth arrest, or induction of caspase-mediated apoptosis coupled with the failure to adhere and to differentiate.
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PMID:Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis. 1104 74

Tumor necrosis factor (TNF)-alpha and TNF-related apoptosis inducing ligand (TRAIL) share a common signaling pathway. Here we show a novel potentiating effect of cadmium on TNF-alpha- or TRAIL-mediated cell death via distinct signaling. TNF-alpha or TRAIL sensitized otherwise resistant NIH3T3 embryo fibroblast cells to death, when exposed to cadmium. The potentiating effects elicited by TNF-alpha or TRAIL on cell death were NF-kappaB- and SAPK/JNK-independent and were not diminished by the expression of Bcl-2. TNF-alpha potentiated the cadmium-induced accumulation of p53 but did not affect expression levels of Bax, Mdm2 and p21(WAF/CIP). A similar pattern of p53 accumulation was also observed in Balbc/3T3 fibroblasts but not in human tumor cell lines, MCF7 and HeLa cells. The synergistic cell death evoked by TNF-alpha and cadmium was attenuated by transient expression of a dominant negative p53(Val135) mutant in NIH3T3 cells and was not observed in p53(-/-) mouse embryo fibroblasts, indicating that p53 accumulation appears to contribute to cell death. In contrast, TRAIL did not further increase the cadmium-induced accumulation of p53 despite its potentiation effects on the cadmium-induced cell death. Expression of p53(Val135) mutant did not reduce TRAIL- and cadmium-mediated cell death. Taken together, these results suggest that TNF-alpha and TRAIL potentiate the cadmium-mediated cell death via distinct p53 expression patterns.
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PMID:Sensitizing effects of cadmium on TNF-alpha- and TRAIL-mediated apoptosis of NIH3T3 cells with distinct expression patterns of p53. 1218 81

Deregulation of cell-cycle G(1)-restriction point control by disruption of Rb-pathway components is a frequent event in cancer. In concert with the inactivation of cell death pathways, such events not only contribute to tumor development but also determine the intrinsic and acquired resistance to cancer therapy and, ultimately, disease prognosis. We previously observed that the cyclin-dependent kinase inhibitor p16(INK4a) and the proapoptotic Bcl-2 homolog Bax are positive prognostic factors and identify patients with good prognosis in esophageal squamous cell carcinoma (SCC). In the present study, we therefore extend our analysis to additional genes controlling the G(1) restriction point and apoptosis, respectively. This retrospective analysis was performed in a cohort of 53 patients undergoing surgery for esophageal SCC with curative intent, i.e., R0 resection. Protein expression profiles of cyclin D1, p16(INK4a), Rb, p21(CIP/WAF-1), p53, Bax and Bcl-2 were analyzed by immunohistochemistry and compared to p53 mutational status, as determined by SSCP-PCR of exons 5-8. Loss of p16(INK4a), Rb, p21(CIP/WAF-1) or Bax and overexpression of cyclin D1 were associated individually with shorter overall survival, while Bcl-2 expression and p53 mutation were not of prognostic relevance. The longest survival was observed in a subgroup of patients whose tumors bore a combination of favorite genotypes, i.e., low cyclin D1 and high Rb, p21(CIP/WAF-1), p16(INK4a) and Bax protein expression. These results show that multigene analyses based on limited sets of functionally linked genes reliably identify patients with good vs. poor prognosis.
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PMID:Multigene analysis of Rb pathway and apoptosis control in esophageal squamous cell carcinoma identifies patients with good prognosis. 1247 59

Resveratrol, which is found in grapes and wine, has been reported to have a variety of important pharmacological effects including anti-inflammatory, anti-platelet, and anti-carcinogenetic properties. In this study, using the human breast cancer cell line MCF-7, we have analyzed a possible mechanism by which resveratrol could interfere with cell cycle control and induce cell death. Resveratrol treatment of MCF-7 cells resulted in a dose-dependent inhibition of the cell growth and the cells accumulated at the S phase transition of the cell cycle at low concentrations, but high concentrations do not induce S phase accumulation. The anti-proliferative effects of resveratrol were associated with a marked inhibition of cyclin D and cyclin-dependent kinase (Cdk) 4 proteins, and induction of p53 and Cdk inhibitor p21WAF1/CIP. Growth suppression by resveratrol was also due to apoptosis, as seen by the appearance of a sub-G1 fraction and chromatin condensation. In addition, the apoptotic process involves activation of caspase-9, a decrease of Bcl-2 as well as Bcl-XL levels, and an increase of Bax levels.
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PMID:Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells. 1471 81

The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using cdk4r24c mutant alleles that confer resistant to INK4 inhibitors) and p21(Waf1/Cip1) in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that cdk4r24c mediates resistance to p15(INK4B)/p16(INK4A) that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although cdk4r24c and p21 loss cooperate in H-ras(V12)/c-myc-induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, p21(-/-); cdk4r24c MEFs expressing H-ras(V12) and c-myc display detachment-induced apoptosis and are transformed by c-myc, H-ras(V12), and Bcl-2. We conclude that the INK4 family and p21 loss cooperate in promoting pRb inactivation, cell immortalization, and H-ras(V12)/c-myc-induced loss of contact inhibition. In addition, absence of pRb function renders H-ras(V12) + c-myc-transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein-deficient cells requires apoptotic suppression.
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PMID:p21 loss cooperates with INK4 inactivation facilitating immortalization and Bcl-2-mediated anchorage-independent growth of oncogene-transduced primary mouse fibroblasts. 1748 23

The growth-inhibitory effects of the astaxanthin-rich Haematococcus pluvialis were studied in HCT-116 colon cancer cells. H. pluvialis extract (5-25 microg/ml) inhibited cell growth in a dose- and time-dependent manner, by arresting cell cycle progression and by promoting apoptosis. At 25 microg/ml of H. pluvialis extract, an increase of p53, p21(WAF-1/CIP-1) and p27 expression (220%, 160%, 250%, respectively) was observed, concomitantly with a decrease of cyclin D1 expression (58%) and AKT phosphorylation (21%). Moreover, the extract, at the same concentration, strongly up-regulated apoptosis by modifying the ratio of Bax/Bcl-2 and Bcl-XL, and increased the phosphorylation of p38, JNK, and ERK1/2 by 160%, 242%, 280%, respectively. Growth-inhibitory effects by H. pluvialis were also observed in HT-29, LS-174, WiDr, SW-480 cells. This study suggests that H. pluvialis may protect from colon cancer.
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PMID:Growth-inhibitory effects of the astaxanthin-rich alga Haematococcus pluvialis in human colon cancer cells. 1942 15

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers.
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PMID:Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone-resistant prostate cancer PC-3 cells. 2016 59


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