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)

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

The CD40 molecule transmits a signal that abrogates apoptosis induced by ligation of the antigen receptor (BCR) in both primary B cells and B-cell lines such as WEHI-231. Expression of Bcl-xL and A1, antiapoptotic members of the Bcl-2 family, is enhanced by CD40 ligation, and is suggested to mediate CD40-induced B-cell survival. CD40 ligation also promotes cell cycle progression by increasing the levels of cyclin-dependent kinases (CDKs) required for cell cycle progression, and reducing expression of the CDK inhibitor p27(kip1). Here we demonstrate that cell cycle inhibition by retrovirus-mediated p27(kip1) expression does not modulate the levels of Bcl-xL or A1, but significantly reduces the survival of BCR-ligated WEHI-231 cells by CD40 ligation. This indicates that cell cycle progression is crucial for CD40-mediated survival of B cells.
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PMID:Involvement of cell cycle progression in survival signaling through CD40 in the B-lymphocyte line WEHI-231. 1464 41

Glucocorticoids (GC) control cell cycle progression and induce apoptosis in cells of the lymphoid lineage. Physiologically, these phenomena have been implicated in regulating immune functions and repertoire generation. Clinically, they form the basis of inclusion of GC in essentially all chemotherapy protocols for lymphoid malignancies. In spite of their significance, the molecular mechanisms underlying the anti-leukemic GC effects and the clinically important phenomenon of GC resistance are still unknown. This review summarizes recent findings related to GC-induced apoptosis, cell cycle arrest, and GC resistance with particular emphasis on acute lymphoblastic leukemia (ALL). We hypothesize that under conditions of physiological Bcl-2 expression, GC might induce classical programmed cell death by directly perturbing the Bcl-2 rheostat. In the presence of anti-apoptotic Bcl-2 proteins, cell death might result from accumulating catabolic and/or other detrimental GC effects driven by, and critically dependent on, GC receptor (GR) autoinduction. Although still controversial, there is increasing evidence for release of apoptogenic factors through pores in the outer mitochondrial membrane, rather than deltapsiloss-dependent membrane rupture, with maintenance of mitochondrial function at least in the early phase of the death response. GC-induced cell cycle arrest in ALL cells appears to be independent of apoptosis induction and vice versa, and critically depends on repression of both cyclin-D3 and c-myc followed by increased expression of the cyclin-dependent kinase inhibitor, p27Kip1. Since development of GC-resistant clones requires both cell cycle progression and survival, GC resistance might frequently result from structural or regulatory defects in GR expression, perhaps the most efficient means to target both pathways concurrently.
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PMID:A conceptual view on glucocorticoid-lnduced apoptosis, cell cycle arrest and glucocorticoid resistance in lymphoblastic leukemia. 1468 92

We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase II. The cyclin L2 protein contains an N-terminal "cyclin box" and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase II and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.
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PMID:Cyclin L2, a novel RNA polymerase II-associated cyclin, is involved in pre-mRNA splicing and induces apoptosis of human hepatocellular carcinoma cells. 3259 51

The c-Jun NH(2)-terminal kinase (JNK) subgroup of mitogen-activated protein kinases has been implicated largely in stress responses, but an increasing body of evidence has suggested that JNK also plays a role in cell proliferation and survival. We examined the effect of JNK inhibition, using either SP600125 or specific antisense oligonucleotides, on cell proliferation and cell cycle progression. SP600125 was selective for JNK in vitro and in vivo versus other kinases tested including ERK, p38, cyclin-dependent protein kinase 1 (CDK1), and CDK2. SP600125 inhibited JNK activity and KB-3 cell proliferation with the same dose dependence, suggesting that inhibition of proliferation was a direct consequence of JNK inhibition. Inhibition of proliferation by SP600125 was associated with an increase in the G(2)-M and apoptotic fractions of cells but was not associated with p53 or p21 induction. Antisense oligonucleotides to JNK2 but not JNK1 caused highly significant inhibition of cell proliferation. Wild-type mouse fibroblasts responded similarly with proliferation inhibition and apoptosis induction, whereas c-jun(-/-) fibroblasts were refractory to the effects of SP600125, suggesting that JNK signaling to c-Jun is required for cell proliferation. Studies in synchronized KB-3 cells indicated that SP600125 delayed transit time through S and G(2)-M phases. Correspondingly, JNK activity increased in late S phase and peaked in late G(2) phase. During synchronous mitotic progression, cyclin B levels increased concomitant with phosphorylation of c-Jun, H1 histone, and Bcl-2. In the presence of SP600125, mitotic progression was prolonged, and c-Jun phosphorylation was inhibited, but neither H1 nor Bcl-2 phosphorylation was inhibited. However, the CDK inhibitor roscovitine inhibited mitotic Bcl-2 phosphorylation. These results indicate that JNK, and more specifically the JNK2 isoform, plays a key role in cell proliferation and cell cycle progression. In addition, conclusive evidence is presented that a kinase other than JNK, most likely CDK1 or a CDK1-regulated kinase, is responsible for mitotic Bcl-2 phosphorylation.
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PMID:Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: evidence that mitotic Bcl-2 phosphorylation is JNK-independent. 1470 47

A431 resistant variants to epoxomicin (EXM) were established, showing 4.0-6.7 times more resistance to EXM than parental A431P. Both variants demonstrated increased expression of the beta-subunit molecules of 26S proteasome with approximately 2.5 times increased activity. In variant cells, cyclin B and P34cdc2 were over-expressed, whereas P21WAF1 was expressed at a similar level to A431P. Because of the proteasome inhibitor acting as a G2/M blocker, results are to the advantage of resistant cells proliferating in the presence of an inhibitor under a severe environment. Variant cells showed increased expression of epidermal growth factor receptor (EGFR) and decreased expression of mRNA, but also slight accumulation of protein of c-Cbl, which is a negative regulator of EGFR possessing ubiquitin ligase activity to desensitize EGF signaling. UbcH7, acting intimately with c-Cbl, was decreased in level compared to A431P. These phenomena can be regarded as one of the causes of prevention of c-Cbl-mediated down-regulation of EGFR in variant cells, enabling them to live. The anti-apoptotic Bcl-2 mainly consisted of a phosphorylated form with resistance to proteasomal degradation, suggesting that Bcl-2 phosphorylation occurred independently of its apoptotic function. Variant cells showed resistance not only to EXM, but to the 5 proteasome inhibitors, while demonstrating collateral sensitivity to doxorubicin.
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PMID:Establishment and some characteristics of epoxomicin (a proteasome inhibitor) resistant variants of the human squamous cell carcinoma cell line, A431. 1471 20

A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells. At 20 microM, Roscovitine induced apoptosis in 21 of 28 B-CLL samples and was equally effective in zap-70-positive or -negative samples. Caspase-3 was cleaved in B-CLL cells exposed to Roscovitine and the pancaspase inhibitor z.VAD.fmk-blocked Roscovitine-induced apoptosis. Expression of the proapoptotic protein Bak was increased and Bax cleavage and conformational change was observed in Roscovitine-treated B-CLL cells. Antiapoptotic proteins Mcl-1 and XIAP were downregulated, but the expression of Bcl-2 remained unchanged. In contrast to previous reports in cancer cell lines, Roscovitine treatment was not accompanied by nuclear accumulation of p53. Cyc202 (R-Roscovitine) is in early clinical trials in cancer patients. Given its powerful effects on zap-70-positive and -negative B-CLL cells, but not on normal lymphocytes, Roscovitine might be an attractive drug to be tested in this incurable disease.
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PMID:Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. 1497 97

Natural products regulate cell growth in response to oncogene activation that induces cell cycle arrest and apoptosis in tumor cell lines. We investigated the mechanisms of caspase activation in human malignant melanoma, A375-S2 cells, by the natural product shikonin, which was isolated from the plant Lithospermum erythrorhizon SIEB. et ZUCC. Shikonin inhibited cell growth in a time- and dose-dependent manner, which might be mediated through up-regulation of p53 and down-regulation of cyclin-dependent protein kinase 4. Caspase activation was detected in shikonin-induced cell apoptosis, which involved in a post-mitochondrial caspase-9-dependent pathway. Decreased Bcl-2 protein levels and increased Bax protein levels were positively correlated with elevated expression of p53 protein. Apoptosis-inducing factor, another apoptotic protein of mitochondria, partially contributed to shikonin-induced release of cytochrome c. Taken together, shikonin-induced DNA damage activates p53 and caspase-9 pathways.
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PMID:p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cells. 1497 55

Olomoucine and Roscovitine are two ATP-competing compounds described as specific inhibitors of cyclin-dependent kinases (CDK). Both drugs showed to induce apoptosis in SH-SY5Y, a neuroblastoma-derived cell line. In these cells, neither Bcl-2 nor Bcl-XL overexpression conferred any resistance to both drugs. However, a partial protective effect was detected when cells were treated with a general inhibitor of caspases (zVADfmk), cycloheximide (CHX), or actinomycin D (DAct). Interestingly, a synergism in cell protection was observed between zVADfmk and macromolecular synthesis inhibitors, thus suggesting different apoptotic pathways in distinct subpopulations of the cell culture. On the other hand, no lethality was found when cells were treated with either PD98059 or UO126. This discarded Erk1/Erk2 inhibition as the cause of apoptosis. Furthermore, SH-SY5Y cells became resistant to either Olomoucine or Roscovitine upon the induction of differentiation. This resistance correlated with the extent of differentiation and, therefore, the number of cells entering a quiescent state. In conclusion, our results seem to support a role for CDK inhibition as the cause of the apoptotic process triggered by Olomoucine and Roscovitine. In addition, we contribute to define a promising profile as anticancer drugs for both compounds, at least in the treatment of neuroblastoma.
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PMID:Cell differentiation, caspase inhibition, and macromolecular synthesis blockage, but not BCL-2 or BCL-XL proteins, protect SH-SY5Y cells from apoptosis triggered by two CDK inhibitory drugs. 1505 86

Ganoderma lucidum (Reishi), an oriental medical mushroom, has been widely used in Asian countries for centuries to prevent or treat different diseases, including cancer. However, the mechanism(s) responsible for the effects of Ganoderma lucidum on cancer cells remain to be elucidated. We have previously demonstrated that Ganoderma lucidum down-regulated the expression of NF-kappaB-regulated urokinase plasminogen activator (uPA) and uPA receptor (uPAR), which resulted in suppression of cell migration of highly invasive human breast and prostate cancer cells. In this study, we investigated the effects of Ganoderma lucidum on cell proliferation, cell cycle, and apoptosis in human prostate cancer cells PC-3. Our data demonstrate that Ganoderma lucidum inhibits cell proliferation in a dose- and time-dependent manner by the down-regulation of expression of cyclin B and Cdc2 and by the up-regulation of p21 expression. The inhibition of cell growth was also demonstrated by cell cycle arrest at G2/M phase. Furthermore, Ganoderma lucidum induced apoptosis of PC-3 cells with a slight decrease in the expression of NF-kappaB-regulated Bcl-2 and Bcl-xl. However, the expression of proapoptotic Bax protein was markedly up-regulated, resulting in the enhancement of the ratio of Bax/Bcl-2 and Bax/Bcl-xl. Thus, Ganoderma lucidum exerts its effect on cancer cells by multiple mechanisms and may have potential therapeutic use for the prevention and treatment of cancer.
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PMID:Ganoderma lucidum inhibits proliferation and induces apoptosis in human prostate cancer cells PC-3. 1506 30


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