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

Results of treatment in childhood acute lymphoblastic leukaemia (ALL) remain unsatisfactory because relapses occur even after high-dose chemotherapy. Corticosensitivity is used in numerous therapeutic trials as a prognostic factor for treatment choice. The aim of this study was to evaluate the role of cell cycle regulatory protein expression before and during the first 48 h of corticotherapy for predicting corticosensitivity. Fifty-two children presenting with ALL were studied at diagnosis and during the first 48 h of treatment for cell proliferation and apoptosis level by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by means of Western blot. Glucocorticoids induced a significant decrease in the percentage of cells in S-phase and in CDK1, CDK4 and CDK6 expression and an increase in the percentage of cells in subG1 peak. Two criteria for corticosensitivity were used: (i) the number of blast cells after 7 d of treatment with a threshold at 1 x 109/l (usual criterion), (ii) the J8/J1 blast cell ratio, which is independent from initial leucocytosis. Bcl-2 expression at diagnosis was the best predictive variable for the usual corticosensitivity criterion in B- and T-cell ALL. For the second criterion, in B-cell ALL, p21waf1 expression at diagnosis was the sole (albeit poorly) predictive variable, whereas bcl-2 remained of high interest in T-cell ALL. Interestingly, these proteins, bcl-2 and p21waf1, are associated with prolonged cell lifespan and their increased expression is often linked to poor response to cytotoxic drugs. Such preliminary results call for subsequent studies on large independent sets of T-cell and B-cell lineage ALL in order to confirm the J8/J1 blast cell ratio value as well as the role of bcl-2 and p21waf1 expression in predicting corticosensitivity.
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PMID:Role of BCL-2 and cell cycle regulatory proteins for corticosensitivity assessment in childhood acute lymphoblastic leukaemia. 1084 89

Exposure of LNCaP prostate cancer cells to Ukrain (NSC-631570), a novel semisynthetic drug from Chelidonium majus L., results in cell growth inhibition which is concomitant with apoptosis. After 24 h treatment with 3.5 microM of Ukrain as many as 73% cells were found in the G2/M phase. However, at higher drug concentrations (7 microM and 17.5 microM) the changes in cell phase distribution were less dramatic but cell accumulation in the G2/M phase was still evident. The rate of apoptotic cells rose steadily with increased drug concentration in a dose-dependent manner and reached 20% at a dosage of 17.5 microM. To investigate whether the cell cycle control mechanisms are affected in response to Ukrain, we analyzed the expression levels of some cyclins, cyclin-dependent kinases (CDK) and apoptosis-related proteins in drug treated cancer cells. Western blot experiments revealed alterations in levels of CDK1 and CDK2, after treatment. Up-regulation of the CDK inhibitor p27 was observed, which may lead to G2/M cell accumulation, but no substantial changes in expression of Bcl-2 and Bax proteins were found.
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PMID:Induced apoptosis in human prostate cancer cell line LNCaP by Ukrain. 1134 20

The role of Bcl-2 in photodynamic therapy (PDT) is controversial, and some photosensitizers have been shown to induce Bcl-2 degradation with loss of its protective function. Hypericin is a naturally occurring photosensitizer with promising properties for the PDT of cancer. Here we show that, in HeLa cells, photoactivated hypericin does not cause Bcl-2 degradation but induces Bcl-2 phosphorylation in a dose- and time-dependent manner. Bcl-2 phosphorylation is induced by sublethal PDT doses; increasing the photodynamic stress promptly leads to apoptosis, during which Bcl-2 is neither phosphorylated nor degraded. Bcl-2 phosphorylation involves mitochondrial Bcl-2 and correlates with the kinetics of a G(2)/M cell cycle arrest, preceding apoptosis. The co-localization of hypericin with alpha-tubulin and the aberrant mitotic spindles observed following sublethal PDT doses suggest that photodamage to the microtubule network provokes the G(2)/M phase arrest. PDT-induced Bcl-2 phosphorylation is not altered by either the overexpression or inhibition of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH(2)-terminal protein kinase 1 (JNK1) nor by inhibiting the extracellular signal-regulated kinases (ERKs) or protein kinase C. By contrast, Bcl-2 phosphorylation is selectively suppressed by the cyclin-dependent protein kinase (CDK)-inhibitor roscovitine, completely blocked by the protein synthesis inhibitor cycloheximide and enhanced by the overexpression of CDK1, suggesting a role for this pathway. However, in an in vitro kinase assay, active CDK1/cyclin B1 complex failed to phosphorylate immunoprecipitated Bcl-2, suggesting that this protein kinase may not directly modify Bcl-2. Mutation of serine-70 to alanine in Bcl-2 abolishes PDT-induced phosphorylation and restores the caspase-3 activation to the same levels of the vector-transfected cells, indicating that Bcl-2 phosphorylation may be a signal to delay apoptosis in G(2)/M phase-arrested cells.
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PMID:Phosphorylation of Bcl-2 in G2/M phase-arrested cells following photodynamic therapy with hypericin involves a CDK1-mediated signal and delays the onset of apoptosis. 1210 Nov 83

We have examined the effects of the CDK1 inhibitor CGP74514A on cell cycle- and apoptosis-related events in human leukemia cells. An 18-hr exposure to 5 microM CGP74514A induced mitochondrial damage (i.e., loss of Delta psi(m)) and apoptosis in multiple human leukemia cell lines (e.g., U937, HL-60, KG-1, CCRF-CEM, Raji, and THP; range 30-95%). In U937 cells, CGP74514A- induced apoptosis (5 microM) became apparent within 4 hr and approached 100% by 24 hr. The pan- caspase inhibitor Boc-fmk and the caspase-8 inhibitor lETD-fmk opposed CGP74514A-induced caspase-9 activation and PARP degradation, but not cytochrome c or Smac/DIABLO release. CGP74514A-mediated apoptosis was substantially blocked by ectopic expression of full-length Bel- 2, a loop-deleted mutant Bcl-2, and Bcl-x(L). CGP74514A treatment (5 microM; 18 hr) resulted in increased p21(CIP1) expression, p27(KIP1) degradation, diminished E2F1 expression, and dephosphorylation of p34(CDC2). It also induced early (i.e., within 2 hr) inhibition of CDK1 activity and dephosphorylation of pRb, followed by pRb degradation, but did not block pRb phosphorylation at CDK2- and CDK4- specific sites. These findings indicate that the selective CDK1 inhibitor, CGP74514A, induces complex changes in cell cycle-related proteins in human leukemia cells accompanied by extensive mitochondrial damage, caspase activation, and apoptosis.
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PMID:Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. 1242 20

Diadenosine oligophosphates (Ap(n)A) have been proposed to function as intracellular and extracellular signaling molecules in animal cells. Here, we have examined the cellular and molecular mechanisms underlying the induction of apoptosis by diadenosine 5',5"'-P(1),P(4)-tetraphosphate (Ap(4)A). We have shown a dose-dependent apoptotic response in cells treated with Ap(4)A. Flow cytometric analysis indicated an involvement of Ap(4)A at an early stage of G1/S arrest. No difference in the amount of p21(waf1) was observed in HL60 cells treated with Ap(4)A compared to control cells. The level of retinoblastoma protein (pRb) dropped dramatically when apoptosis was extensive. The cleavage of pRb was abrogated if Ap(4)A-treated cells were incubated with general caspase inhibitor zVAD-fmk. Ap(4)A also induced a profound decrease in the level of the Bcl-2 protein. The lack of effect of Ap(4)A on CDK1 activity indicated that Ap(4)A is not involved in "aberrant mitosis". We suggest that in vivo Ap(4)A may play a significant role in tumor growth suppression by inducing apoptosis.
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PMID:The involvement of diadenosine 5',5"'-P1,P4-tetraphosphate in cell cycle arrest and regulation of apoptosis. 1250 98

Activation of the c-Jun N-terminal kinase (JNK) pathway is suggested to be required for neuronal apoptosis. We investigated the role of JNK on phosphorylation of c-Jun, Bcl-2, and apoptotic translocation of cytochrome c (cyt c) in UV-induced apoptosis in human neuroblastoma SH-SY5Y cells. We confirm that UV irradiation induces both apoptosis and necrosis in SH-SY5Y cells and that phosphorylation of JNK at Thr183/Tyr185 in SH-SY5Y cells treated with UV is an early event preceding apoptosis. We also demonstrate that phosphorylation of c-Jun at Ser63 is an early event coinciding with JNK activation, and that the phosphorylation of c-Jun is partially prevented by the JNK inhibitor SP600125. Despite the use of SP600125, the amount of cyt c released into the cytoplasm is not diminished and SP600125 is also unable to decrease the extent of UV-induced apoptosis. These data support the hypothesis that in this system, UV-induced apoptosis is not dependent exclusively on JNK activation. Possible involvement of cyclin-dependent kinases (CDKs) in c-Jun phosphorylation at Ser63 was excluded by pretreating UV-irradiated SH-SY5Y cells with the CDK1/2/5 inhibitor roscovitine.
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PMID:UV-induced apoptosis in SH-SY5Y cells: contribution to apoptosis by JNK signaling and cytochrome c. 1538 28

Bcl-xL and Bcl-2 are phosphorylated in response to microtubule inhibitors, but the kinase(s) responsible and the functional significance have remained unclear. In this study, we investigated the characteristics of Bcl-xL and Bcl-2 phosphorylation in KB-3 carcinoma cells treated with vinblastine. In both asynchronous and synchronous cell cultures, Bcl-xL and Bcl-2 underwent a well-defined and coordinated cycle of phosphorylation and dephosphorylation, with a lengthy period of phosphorylation preceding apoptosis induction, and with dephosphorylation closely correlated with initiation of apoptosis. Internally, validated inhibitors of JNK, ERK, p38(MAPK), or CDK1 failed to inhibit vinblastine-induced phosphorylation of Bcl-xL or Bcl-2. In vitro, Bcl-xL and Bcl-2 were poor substrates relative to c-Jun and ATF2 for active recombinant JNK1. Both Bcl-xL and Bcl-2 were localized primarily to the mitochondrial fraction in both control and vinblastine-treated cells, indicating that phosphorylation did not promote subcellular redistribution. Bcl-xL kinase activity was demonstrated in mitochondrial extracts from vinblastine-treated, but not control, cells. These findings suggest that phosphorylation of these key antiapoptotic proteins may be catalysed by a novel or unsuspected kinase that is activated or induced in response to microtubule damage. Furthermore, the same kinase and phosphatase system may be operating in tandem on both proteins, and phosphorylation appears to maintain their antiapoptotic function, whereas dephosphorylation may trigger apoptosis. These results provide evidence for a novel signaling pathway connecting microtubule damage to apoptosis induction, and help to clarify some of the controversy concerning the role of Bcl-2 phosphorylation in microtubule inhibitor-induced apoptosis.
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PMID:Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction. 1553 23

The development and progression of epithelial cancers are the result of an imbalance in signals promoting and inhibiting cellular proliferation and apoptosis. The aim of this study is to evaluate the expression of cell-cycle and apoptosis regulators and correlate them with clinical outcome in the most frequent carcinomas, in order to establish common prognostic biomarkers independent of cancer origin. Using tissue microarrays (TMAs), we have analysed the immuno-expression of Ki-67, Bcl-2, Bax, cyclin D1, cyclin D3, CDK1, CDK2, CDK6, p16, p21, and p27 in a series of 205 carcinomas of the large bowel, breast, lung and prostate (80, 73, 37 and 15 cases, respectively). By univariate analysis, positivity for p27, p16 and Bcl-2 was associated with better overall survival (P<0.0135, P<0.0442 and P<0.0001, respectively). The risk of mortality was 2.3-fold greater in patients without Bcl-2 expression. TMA immunohistochemical analysis identified a subset of epithelial cancers with overlapping alterations in cell-cycle checkpoints, apoptosis regulators and tumour suppressor pathways. We found that in most common epithelial cancers, regardless of origin, Bcl-2 appears to be the key biological factor influencing clinical behaviour.
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PMID:Cell-cycle-associated markers and clinical outcome in human epithelial cancers: a tissue microarray study. 1627 50

Peptidylarginine deiminases (PADIs) convert peptidylarginine into citrulline via posttranslational modification. One member of the family, PADI4, plays an important role in immune cell differentiation and cell death. To elucidate the participation of PADI4 in haematopoietic cell death, we examine whether inducible overexpression of PADI4 enhances the apoptotic cell death. PADI4 reduced the viability in a dose- and time-dependent manner of human leukemia HL-60 cells and human acute T leukemia Jurkat cells. The apoptosis-inducing activities were determined by nuclear condensation, DNA fragmentation, sub-G1 appearance, loss of mitochondrial membrane potential (delta psi(m)), release of mitochondrial cytochrome c into cytoplasm and proteolytic activation of caspase 9 and 3. Following PADI4 overexpression, cells arrest in G1 phase significantly before their entrance into apoptotic cell death. PADI4 increases tumor suppressor p53 and its downstream p21 to control cell cycle. In the detections of protein expression and kinase activity, all protein levels of cyclin-dependent kinases (CDKs) and cyclins are not reduced except cyclin D, however, CDK2 (G1 entry S phase) and CDK1 (G2 entry M phase) enzyme activities are inhibited by conditionally inducible PADI4. p53 also expands its other downstream Bax to induce cytochrome c release from mitochondria. According to these data, we suggest that PADI4 induces apoptosis mainly through cell cycle arrest and mitochondria-mediated pathway. Furthermore, p53 features in PADI4-induced apoptosis by increasing intracellular p21 to control cell cycle and by Bax accumulation to decline Bcl-2 function, destroy delta psi(m), release cytochrome c to cytoplasm and activate the caspase cascade.
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PMID:Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells. 1650 57


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