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)

Flavopiridol (NSC 649890; Behringwerke L86-8275, Marburg, Germany), is a potent inhibitor of cyclin dependent kinases (CDKs) 1, 2, and 4. It has potent antiproliferative effects in vitro and is active in tumor models in vivo. While surveying the effect of flavopiridol on cell cycle progression in different cell types, we discovered that hematopoietic cell lines, including SUDHL4, SUDHL6 (B-cell lines), Jurkat, and MOLT4 (T-cell lines), and HL60 (myeloid), displayed notable sensitivity to flavopiridol-induced apoptosis. For example, after 100 nmol/L for 12 hours, SUDHL4 cells displayed a similar degree of DNA fragmentation to that shown by the apoptosis-resistant PC3 prostate carcinoma cells only after 3,000 nmol/L for 48 hours. After exposure to 1,000 nmol/L flavopiridol for 12 hours, typical apoptotic morphology was observed in SUDHL4 cells, but not in PC3 prostate carcinoma cells despite comparable potency (SUDHL4: 120 nmol/L; PC3: 203 nmol/L) in causing growth inhibition by 50% (IC50). Flavopiridol did not induce topoisomerase I or II cleavable complex activity. A relation of p53, bcl2, or bax protein levels to apoptosis in SUDHL4 was not appreciated. While flavopiridol caused cell cycle arrest with decline in CDK1 activity in PC3 cells, apoptosis of SUDHL4 cells occurred without evidence of cell cycle arrest. These results suggest that antiproliferative activity of flavopiridol (manifest by cell cycle arrest) may be separated in different cell types from a capacity to induce apoptosis. Cells from hematopoietic neoplasms appear in this limited sample to be very susceptible to flavopiridol-induced apoptosis and therefore clinical trials in hematopoietic neoplasms should be of high priority.
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PMID:Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. 942 98

Physiological cell deaths occur ubiquitously throughout biology and have common attributes, including apoptotic morphology with mitosis-like chromatin condensation and prelytic genome digestion. The fundamental question is whether a common mechanism of dying underlies these common hallmarks of death. Here we describe evidence of such a conserved mechanism in different cells induced by distinct stimuli to undergo physiological cell death. Our genetic and quantitative biochemical analyses of T- and B-cell deaths reveal a conserved pattern of requisite components. We have dissected the role of cysteine proteases (caspases) in cell death to reflect two obligate classes of cytoplasmic activities functioning in an amplifying cascade, with upstream interleukin-1beta-converting enzyme-like proteases activating downstream caspase 3-like caspases. Bcl-2 spares cells from death by punctuating this cascade, preventing the activation of downstream caspases while leaving upstream activity undisturbed. This observation permits an operational definition of the stages of the cell death process. Upstream steps, which are necessary but not themselves lethal, are modulators of the death process. Downstream steps are effectors of, and not dissociable from, actual death; the irreversible commitment to cell death reflects the initiation of this downstream phase. In addition to caspase 3-like proteases, the effector phase of death involves the activation in the nucleus of cell cycle kinases of the cyclin-dependent kinase (Cdk) family. Nuclear recruitment and activation of Cdk components is dependent on the caspase cascade, suggesting that catastrophic Cdk activity may be the actual effector of cell death. The conservation of the cell death mechanism is not reflected in the molecular identity of its individual components, however. For example, we have detected different cyclin-Cdk pairs in different instances of cell death. The ordered course of events that we have observed in distinct cases reflects essential thematic elements of a conserved sequence of modulatory and effector activities comprising a common pathway of physiological cell death.
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PMID:Commitment and effector phases of the physiological cell death pathway elucidated with respect to Bcl-2 caspase, and cyclin-dependent kinase activities. 956 10

Effect of low-density lipoprotein (LDL) on the expression of Bcl-2 as well as cyclin 'D' genes was studied in Receptor 'Ck' (+ve) and Receptor 'Ck'(-ve) human lymphocytes. LDL had no effect upon the elevated levels of Bcl-2 and cyclin 'D' gene products in Receptor 'Ck' (-ve) lymphocytes (from untreated CML patients), whereas in Receptor 'Ck' (+ve) lymphocytes (from normal subjects), the exposure to LDL regulated the level of cyclin 'D' gene product without initiating the expression of bcl-2 gene product. However, blockage of Receptor 'Ck' in normal lymphocytes, through its specific antibody (Ab-RCk) in presence or absence of LDL, resulted in the induction of both cyclin 'D' (at 4 h interval) and bcl-2 (at 12 h interval) gene products. Based upon these results, we propose that Receptor 'Ck' deficiency in cells may inherit defective apoptosis and capacity proliferation leading to leukemic transformation.
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PMID:LDL-dependent regulation of Bcl-2 and cyclin 'D' gene expression in lymphocytes from normal and CML patients. 957 Mar 62

Kaposi's sarcoma-associated herpesvirus or human herpesvirus type 8 (HHV-8) is present in all forms of Kaposi's sarcoma (KS) as well as in primary effusion lymphomas and some cases of Castleman's disease. In KS tissues, HHV-8 is present in endothelial and spindle cells. Current serologic tests suggest that HHV-8 is predominantly found in those at risk of KS and is not as widespread as most other human herpesviruses. HHV-8 encodes various proteins that may play a role in promotion of cellular growth, including cyclin- and G-coupled protein receptor homologues, and anti-apoptotic proteins, including Bcl-2, IL-6 (i.e., interleukin 6), and FLIP (i.e., FLICE inhibitory protein) homologues. In addition, HHV-8 encodes two macrophage inflammatory-like proteins with anti-human immunodeficiency virus and angiogenic potential.
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PMID:Human herpesvirus type 8 and Kaposi's sarcoma. 970 3

Kaposi's sarcoma (KS) is a vascular tumor predominantly found in the immunosuppressed. Epidemiologic studies suggest that an infective agent is the etiologic culprit. Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8 (HHV-8), is a gamma human herpesvirus present in all epidemiologic forms of KS and also in a rare type of a B cell lymphoma, primary effusion lymphoma (PEL). In addition, this virus is present in most biopsies from human immunodeficiency virus (HIV)-associated multicentric Castleman's disease (MCD). MCD is a lymphoproliferative disorder with, like KS, a prominent microvasculature. The genome of KSHV contains the expected open reading frames (ORFs) encoding for enzymes and viral structural proteins found in other herpesviruses, but it also contains an unprecedented number of ORFs pirated during viral evolution from cellular genes. These include proteins that may alter cellular growth (e.g., Bcl-2 and cyclin homologs), induce angiogenesis (e.g., chemokine, chemokine receptor, and cytokine homologs), and regulate antiviral immunity (e.g., CD21 and interferon regulatory factor homologs). No ORF with sequence similarity to the Epstein-Barr nuclear antigens (EBNAs) and latent membrane proteins (LMPs) of Epstein-Barr virus (EBV) is present, but proteins analogous to these in structure and in latent expression are found [e.g., ORF 73 encoding for KSHV latent nuclear antigen (LNA-1) and K12 encoding for a possible latent membrane protein]. Current serologic assays confirm the strong association of infection with KSHV and risk of KS development. The mechanism of how this new virus may trigger the precipitation of KS is still unclear.
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PMID:Kaposi's sarcoma-associated herpesvirus. 970 7

In the medical literature there are frequently conflicting reports on the utility of biological tumour markers available in the clinical management of breast cancer. In this review we analyse current information on the relationships between the most widely investigated breast cancer biological markers including oestrogen and progesterone receptors, p53, Bcl-2, c-erbB-2, cyclin expression, proliferative activity, DNA ploidy and the urokinase plasminogen activation system, as well as their relevance to prognosis and response to clinical treatment. By biological prognostic indicator, we mean a marker that correlates with survival and disease-free survival; the term predictor marker indicates a marker that is capable of predicting tumour sensitivity or resistance to various therapies. Similarly to other authors' experiences, our analysis suggests that oestrogen receptors are weak prognostic indicators and good predictors of response to endocrine therapy. Furthermore, there are consistent data suggesting that proliferation indices are good indicators of prognosis, and that they are directly related to response to chemotherapy and closely related to response to hormonotherapy. On the contrary, there is no evidence or conflicting data for all of the other biological markers. These should be considered in the context of randomized trials in order to precisely define their prognostic and predictive roles. p53 and c-erbB-2 seem to be the most promising factors, but their use in routine practice still needs validation.
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PMID:Prognosis and prediction of response in breast cancer: the current role of the main biological markers. 985 25

Bcl-2 is present in a cytoplasmic distribution in cells that express high levels of this oncoprotein. In contrast, using immunocytochemistry in cells expressing low levels of bcl-2, such as KB human carcinoma cells, we and others have shown that bcl-2 is present on the surface of mitotic chromosomes. However, monoclonal antibodies reactive with an epitope representing amino acids 41-54 of the bcl-2 sequence did not detect bcl-2 in other phases of the cell cycle. This study extended those earlier findings to determine if bcl-2 was expressed as a cyclin or if this pattern was an artifact of immunocytochemistry. Immunofluorescence studies in several other human cell lines showed the same mitotic distribution of bcl-2. Other studies using flow cytometry also showed selective mitotic phase detection of bcl-2. A comparison of available commercial antibodies showed that, in spite of reactivity with denatured bcl-2 on Western blots, clear reactivity with bcl-2 in fixed cells was found only with those reactive with the (a.a. 41-54) epitope. With RNase protection and Western blot analyses, cells synchronized at various stages of the cell cycle showed constant levels of bcl-2 mRNA and protein. Analysis of bcl-2 using Western blots showed a band with the same apparent molecular weight as that seen in comparison with authentic bcl-2 overexpressed in the cytoplasm. The retention of bcl-2 on chromosomes in unfixed, permeabilized preparations was influenced by protease treatment, phosphate, and pH. Studies using isolated chromosomes showed that much of the bcl-2 in these cells was attached to chromosomes in mitosis, had the expected molecular weight, and was phosphorylated in the same manner as that seen in whole-cell extracts. These results show that bcl-2 is not a cyclin and that the bcl-2 localized on chromosomes is the same molecule seen by immunoblotting. These results suggest that the reactive (a.a. 41-54) epitope present in bcl-2 is somehow modified or masked in interphase.
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PMID:Mitotic chromosomal bcl-2. I. Stable expression throughout the cell cycle and association with isolated chromosomes. 988 50

Aberrant activation of cell cycle molecules has been postulated to play a role in apoptosis ("catastrophic cell cycle"). Here we show that in noncycling developing thymocytes, the cyclin- dependent kinase Cdk2 is activated in response to all specific and nonspecific apoptotic stimuli tested, including peptide-specific thymocyte apoptosis. Cdk2 was found to function upstream of the tumor suppressor p53, transactivation of the death promoter Bax, alterations of mitochondrial permeability, Bcl-2, caspase activation, and caspase-dependent proteolytic cleavage of the retinoblastoma protein. Inhibition of Cdk2 completely protected thymocytes from apoptosis, mitochondrial changes, and caspase activation. These data provide the first evidence that Cdk2 activity is crucial for the induction of thymocyte apoptosis.
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PMID:The cyclin-dependent kinase Cdk2 regulates thymocyte apoptosis. 1007 79

Pancreatic adenocarcinoma is the fifth leading cause of cancer related deaths in the United States. Treatment for this disease has largely been unsuccessful, which may partly be due to insufficient data regarding the molecular mechanisms of chemotherapeutic drugs currently being used as single agents or in combined modality regimens. In this study, we investigated the molecular mechanisms by which auristatin-PE, a newly developed experimental agent, and gemcitabine, a commercially available anti-cancer agent, exert their inhibitory effects on pancreatic cancer cell lines containing wild-type p53 (HPAC) and mutant p53 (PANC-1). Our results showed that auristatin-PE and gemcitabine inhibited cell growth and induced cell cycle arrest in G2/M and S phase, respectively. Auristatin-PE also induced apoptosis in both cell lines. Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down-regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells. These results suggest that auristatin-PE may induce apoptosis and p21WAF1 expression through p53-dependent or independent pathways, and that up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Furthermore, the up-regulation of p21WAF1 and down-regulation of cyclin B may contribute to the G2/M cell cycle arrest. Combination of auristatin-PE and gemcitabine showed significantly greater inhibition of cell growth and up-regulated expression of p21WAF1 and Bax. From these results, we conclude that the selection of therapeutic agents based on their molecular mechanism may improve therapeutic outcome, and that auristatin-PE may be more effective in the treatment of pancreatic cancer when given in combination with gemcitabine, rather than as a single agent.
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PMID:Induction of growth inhibition and apoptosis in pancreatic cancer cells by auristatin-PE and gemcitabine. 1034 Dec 97

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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PMID:Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. 1037 42


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