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)

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases.
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PMID:Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas. 1078 80

The functional role of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1 in differentiation of human myelomonocytic leukemia cells (U937) exposed to low concentrations of the antimetabolite 1-beta-D-arabino-furanosylcytosine (ara-C) was examined utilizing a cell line stably expressing a p21CIP1 antisense construct. Continuous exposure to 50 nM ara-C led to marked induction of p21CIP1 at 48-72 h in empty-vector control cells but not in their antisense-expressing counterparts (p21AS/F4 and B8). Such treatment induced expression of the myelomonocytic differentiation marker CD11b in approximately 35% of control cells, but no evidence of maturation was noted in antisense-expressing lines. However, antisense-expressing cells exposed to low concentrations of ara-C exhibited a reciprocal increase in apoptosis, manifested by the appearance of cells with classic morphologic features and hypodiploid quantities of DNA, reduced mitochondrial membrane potential (deltapsim), an increase in cytochrome c release into the cytosol, cleavage/activation of procaspases-9 and -3, and degradation of PARP and p27Kip1. Whereas empty-vector control cells exposed to 50 nM ara-C exhibited a decline in Bcl-2 expression, dephosphorylation of pRb, and an initial accumulation in S-phase, antisense-expressing cells did not. However, c-Myc down-regulation induced by low concentrations of ara-C was, if anything, more complete in antisense-expressing cells. Exposure of control but not antisense-expressing cells to ara-C led to phosphorylation/activation of MAP kinase at 24 h; moreover, the specific MEK/MAP kinase inhibitor PD98059 enhanced low-dose ara-C-mediated apoptosis only in wild-type cells. Lastly, exposure to 50 nM ara-C for 72 h resulted in detectable levels of cytoplasmic p21CIP1, a phenomenon associated with resistance to apoptosis, only in empty vector controls. Collectively, these findings demonstrate a functional role for p21CIP1 in leukemic cell maturation induced by low concentrations of ara-C. They also indicate that, as in the case of more conventional differentiation-inducers such as phorbol esters, disruption of the p21CIP1 response after exposure to low concentrations of the cytotoxic drug ara-C prevents leukemic cells from engaging a maturation program, but instead directs them along an apoptotic pathway.
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PMID:Evidence of a functional role for the cyclin-dependent kinase inhibitor p21CIP1 in leukemic cell (U937) differentiation induced by low concentrations of 1-beta-D-arabinofuranosylcytosine. 1099 87

We have compared the anti-proliferative effects of ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA) and their derivatives, HS-1183, HS-1199 and HS-1200, on MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells. While UDCA and CDCA exhibited no significant effect, their novel derivatives inhibited the proliferation of both cell lines in a concentration-dependent manner, concomitant with apoptotic nuclear changes and the increase of a sub-G1 population and DNA fragmentation. Furthermore, we also observed an increase in the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 and cleavages of lamin B and poly(ADP-ribose) polymerase (PARP) in MCF-7 and MDA-MB-231 cells. Cell cycle related proteins, cyclin D1 and D3, as well as retinoblastoma protein (pRb) were down-regulated, while the level of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) was increased in both cancer cells after treatment with novel bile acids. These findings suggest that these cytotoxic effects of novel bile acid derivatives on human breast carcinoma cells were mediated via apoptosis through a p53-independent pathway.
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PMID:Novel bile acid derivatives induce apoptosis via a p53-independent pathway in human breast carcinoma cells. 1116 11

Expression of bcl-2 protein was investigated and correlated with Bax, p53 and Rb proteins, c-erbB-2, EGFR and the proliferation indices PCNA, Ki-67 and MIB1 as well as with the conventional clinicopathological parameters in 95 cases for breast cancer tissue and 20 cases of benign hyperplastic lesions. Bcl-2 and Bax proteins immunoreactivity was detected in normal, hyperplastic and neoplastic breast epithelium. Expression of the bcl-2 protein was detected in 40% of carcinomas (> 10% positive neoplastic cells) and 85.2% of the benign hyperplastic lesions. Bax protein expression was detected in 8.1% of the carcinomas and 5.3% in the hyperplastic group. Rb and p53 proteins were detected in 75.5% and 45.5% of carcinomas. No relationship was observed between bcl-2 expression and patient's age, tumour size, tumour type and grade, lymph node status, Rb protein expression and proliferation indices. However, a strong positive relationship was detected between bcl-2 and Bax (p = 0.008), estrogen (ER) (p = 0.007) and progesterone receptors' (PgR) status (p = 0.0003). An inverse correlation with p53 protein (p = 0.004) was detected. Furthermore, a strong correlation was also observed between pRb and p53 (p = 0.001). The results indicate that in breast cancer bcl-2 protein expression may be under hormonal control. Since the expression is bcl-2 protein was inversely correlated with p53 protein expression, we suggest that bcl-2 may be related with favourable outcome in breast cancer.
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PMID:Immunohistochemical expression of Bcl-2 protein in breast lesions: correlation with Bax, p53, Rb, C-erbB-2, EGFR and proliferation indices. 1120 51

Flavopiridol inhibits phosphokinases. Its activity is strongest on cyclin dependent kinases (cdk-1, -2, -4, -6, -7) and less on receptor tyrosine kinases (EGFR), receptor associates tyrosine kinases (pp60 Src) and on signal transducing kinases (PKC and Erk-1). Although the inhibiting activity of flavopiridol is strongest for cdk, the cytotoxic activity of flavopiridol is not limited to cycling cells. Resting cells are also killed. This fact suggests that inhibition of cdks involved in the control of cell cycle is not the only mechanism of action. Inhibition of cdk's with additional functions (i.e. involved in the control of transcription or function of proteins that do not control cell cycle) may contribute to the antitumoral effect. Moreover, direct and indirect inhibition of receptor activation (EGFR) and/or a direct inhibition of kinases (pp60 Src, PKC, Erk-1) involved in the signal transduction pathway could play a role in the antiproliferative activity of flavopiridol. From pharmacokinetic data in patients it can be concluded that the inhibitory activity (IC50) of flavopiridol on these kinases is in the range of concentrations that might be achieved intracellularly after systemic application of non-toxic doses of flavopiridol. However, no in situ data from flavopiridol treated cells have been published yet that prove that by inhibition of EGFR, pp60 Src, PKC and/or Erk-1 (in addition to inhibition of cdk's) flavopiridol is able to induce apoptosis. Thus many questions regarding the detailed mechanism of antitumoral action of flavopiridol are still open. For the design of protocols for future clinical studies this review covers the essential information available on the mechanism of antitumoral activity of flavopiridol. The characteristics of this antitumoral activity include: High rate of apoptosis, especially in leukemic cells; synergy with the antitumoral activity of many cytostatics; independence of its efficacy on pRb, p53 and Bcl-2 expression; lack of interference with the most frequent multidrug resistance proteins (P-glycoprotein and MRP-190); and a strong antiangiogenic activity. Based on these pharmacological data it can be concluded that flavopiridol could be therapeutically active in tumor patients: independent on the genetic status of their tumors or leukemias (i.e. mutations of the pRb and/or p53, amplification of bcl-2); in spite of drug resistance of their tumors induced by first line treatment (and caused by enhanced expression of multidrug resistance proteins); in combination with conventional chemotherapeutics preferentially given prior to flavopiridol; and due to a complex mechanism involving cytotoxicity on cycling and on resting tumor cells, apoptosis and antiangiogenic activity. In consequence, flavopiridol is a highly attractive, new antitumoral compound and deserves further elucidation of its clinical potency.
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PMID:Mechanisms of action of flavopiridol. 1131 60

The impact of dysregulation of the cyclin-dependent kinase inhibitor p21WAF1/CIP1/MDA6 has been examined in U937 human monocytic leukemia cells in relation to cell cycle arrest and differentiation following treatment with the histone deacetylase inhibitor sodium butyrate (SB). Cells stably transfected with a p21WAF1/CIP1/MDA6 antisense construct, in marked contrast to their wild-type counterparts, failed to up-regulate p21WAF1/CIP1/MDA6, undergo G1 arrest, or express the maturation marker CD11b when exposed to 1 or 3 mM SB. However, antisense-expressing cells were significantly more susceptible to SB-mediated mitochondrial injury and apoptosis, manifested by increased cytosolic translocation of cytochrome c, activation of pro-caspase 3, and degradation of PARP. Dysregulation of p21WAF1/CIP1/MDA6 did not modify the extent of SB-induced histone acetylation, but did result in cleavage of p27KIP1, Bcl-2 and pRb, as well as diminished levels of full-length underphosphorylated pRb. Finally, dysregulation of p21WAF1/CIP1/MDA6 did not modify SB-mediated down-regulation of E2F-1 or c-Myc, but was associated with enhanced down-regulation of cyclins D1 and E. Together, these findings indicate that in U937 leukemia cells, p21WAF1/CIP1/MDA6 plays a critical functional role in SB-mediated G1 arrest and maturation, and suggest that cells displaying dysregulation of this CDKI respond to SB by engaging a default apoptotic program.
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PMID:Evidence of a functional role for the cyclin-dependent kinase-inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). 1140 41

Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-kappaB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.
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PMID:Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. 1203 41

Interactions between the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) and the cyclin-dependent kinase (CDK) inhibitor flavopiridol (FP) were examined in human leukemia cells. Simultaneous exposure (24 h) of myelomonocytic leukemia cells (U937) to SAHA (1 microM) and FP (100 nM), which were minimally toxic alone (1.5 +/- 0.5% and 16.3 +/- 0.5% apoptosis respectively), produced a dramatic increase in cell death (ie 63.2 +/- 1.9% apoptotic), reflected by morphology, procaspase-3 and -8 cleavage, Bid activation, diminished DeltaPsi(m), and enhanced cytochrome c release. FP blocked SAHA-mediated up-regulation of p21(CIP1) and CD11b expression, while inducing caspase-dependent Bcl-2 and pRb cleavage. Similar interactions were observed in HL-60 and Jurkat leukemic cells. Enhanced apoptosis in SAHA/FP-treated cells was accompanied by a marked reduction in clonogenic surivival. Ectopic expression of either dominant-negative caspase-8 (C8-DN) or CrmA partially attenuated SAHA/FP-mediated apoptosis (eg 45 +/- 1.5% and 38.2 +/- 2.0% apoptotic vs 78 +/- 1.5% in controls) and Bid cleavage. SAHA/FP induced-apoptosis was unaffected by the free radical scavenger L-N-acetyl cysteine or the PKC inhibitor GFX. Finally, ectopic Bcl-2 expression marginally attenuated SAHA/FP-related apoptosis/cytochrome c release, and failed to restore clonogenicity in cells exposed to these agents. Together, these findings indicate that SAHA and FP interact synergistically to induce mitochondrial damage and apoptosis in human leukemia cells, and suggest that this process may also involve engagement of the caspase-8-dependent apoptotic cascade.
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PMID:Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). 1209 58

A clinically relevant dose (2.0 Gy) of ionizing radiation (IR) was employed to determine if subsequent exposure to the protein kinase C (PKC) and Chk 1 inhibitor UCN-01 for 24 h could abrogate IR-induced G2/M arrest and promote apoptosis in U937 leukemic cells ectopically expressing Bcl-2 (U937/Bcl-2). To this end, empty-vector control (U937/pCEP4) and U937/Bcl-2 cells were exposed to two UCN-01 concentrations following IR: i) a 50 nM concentration, which by itself was minimally toxic to both cell lines, and ii) a 150 nM concentration, which modestly induced apoptosis (e.g., ~19%) in control cells after 24 h. The effects of UCN-01 on IR responses were examined in relation to apoptosis induction, suspension culture growth inhibition, loss of clonogenic survival, and cell cycle perturbations. IR (2 Gy) alone minimally induced apoptosis in both U937 transfectant cell lines (e.g., <5% at 24 h in each case). Although UCN-01 failed to potentiate IR-mediated apoptosis at either early (e.g., 24 h) or late (e.g., 72 h) intervals, exposure to 50 or 150 nM UCN-01 resulted in a significant, albeit modest, reduction in proliferation and colony formation in irradiated U937/pCEP4 and U937/Bcl-2 cells. Despite failing to enhance apoptosis, UCN-01 treatment abrogated IR-induced G2/M arrest in both cell lines, an event associated with enhanced activation of cyclin-dependent kinase 1 (cdk1), promotion of G0/G1 arrest, and dephosphorylation of the retinoblastoma protein (pRb). Together, these findings indicate that exposure of U937 cells ectopically-expressing Bcl-2 to the combination of UCN-01 + IR leads to a further reduction in cell proliferation, and that this phenomenon appears to involve a non-apoptotic mechanism.
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PMID:7-hydroxystaurosporine (UCN-01) and ionizing radiation combine to inhibit the growth of Bcl-2-overexpressing U937 leukemia cells through a non-apoptotic mechanism. 1211 31

Cross-linking of the B cell antigen receptor (BCR) on germinal center B cells can induce growth arrest and apoptosis, thereby eliminating potentially autoreactive B cells. Using the Burkitt lymphoma cell line Ramos as a model, we studied the commitment to apoptosis following growth arrest, as well as how triggering of CD40 or addition of tumor necrosis factor (TNF)-alpha can interfere to block cell death. Both BCR triggering and direct induction of growth arrest by sodium butyrate (n-But) caused hypophosphorylation of the retinoblastoma protein (pRb), followed by apoptosis. Interestingly, although CD40 ligation or TNF-alpha efficiently prevented BCR-induced and n-But-induced apoptosis, these co-stimuli did not inhibit, but rather augmented, growth arrest. Analysis of cell cycle regulators showed that each apoptotic and T(h) stimulus distinctly affected cyclins or cyclin-dependent kinase inhibitors, indicating that growth arrest can be uncoupled from apoptosis. BCR ligation and growth arrest activated the intrinsic or mitochondrial route of apoptosis. CD40 ligation and TNF-alpha prevented release of cytochrome c and activation of caspase-3, which could not be explained by effects on the expression of Bcl-2, Bcl-x(L) or Bax. Finally, the onset of BCR-induced apoptosis occurred after 10-12 h and addition of CD40 mAb or TNF-alpha at that point still prevented further execution of apoptosis. We conclude that in mature B cells apoptosis is not an obligatory event following growth arrest. Instead, commitment to apoptosis can be rapidly controlled by T cells via CD40 ligand and TNF-alpha, downstream of the pRb-regulated restriction point of the cell cycle, but prior to mitochondrial cytochrome c release.
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PMID:Prevention of B cell antigen receptor-induced apoptosis by ligation of CD40 occurs downstream of cell cycle regulation. 1220 95


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