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)

The expression of Bcl-2 family proteins (Bcl-2, Bcl-X, Bcl-XL, Bcl-Xs, BAX, BAD, MCL-1) and of Interleukin-1 converting enzyme (ICE)-related proteins (ICE, CPP32, ICH- 1) was analyzed in acute leukemia cells by flow cytometry. Most proteins studied were detectable in cell lines such as KG1a, HL60, K562 (myeloblastic), REH, RAJI and MOLT4 (lymphoblastic) and VAL (B-cell lymphoma). However, BCL-Xs and BAK were weakly expressed in K562, as were Bcl-X, BAD and BAK in the VAL line. In acute myeloid leukemia (66 cases studied), the proteins were expressed in most cases in a high percentage of cells, especially BAX and CPP32, without correlation with hematological characteristics. However, Bcl-2 was expressed in a higher percentage of cells in FAB M1 and M5 cases, and in CD34-positive cases, whereas Bcl-Xs was more frequently expressed in M3 cases. No differences were observed regarding fluorescence intensity. Higher percentages of Bcl-2-positive cells were associated with low remission rate, while expression of Bcl-Xs was predictive of high remission rate. In acute lymphoblastic leukemia (36 cases), all proteins studied were expressed in a majority of cases. Bcl-Xs was more frequently detected in T-cell type, and was also associated with a higher remission rate. These results suggest that apoptosis-controlling proteins may have a role in the pathogenesis and response to therapy of acute leukemia.
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PMID:Expression of apoptosis-controlling proteins in acute leukemia cells. 1034 77

Manganese ions block apoptosis of phagocytes induced by various agents. The prevention of apoptosis was attributed to the activation of manganous superoxide dismutase (Mn-SOD) and to the antioxidant function of free Mn2+ cations. However, the effect of Mn2+ on B cell apoptosis is not documented. In this study, we investigated the effects of Mn2+ on the apoptotic process in human B cells. We observed that Mn2+ but not Mg2+ or Ca2+, inhibited cell growth and induced apoptosis of activated tonsilar B cells, Epstein Barr virus (EBV)-negative Burkitt's lymphoma cell lines (BL-CL) and EBV-transformed B cell lines (EBV-BCL). In the same conditions, no apoptosis was observed in U937, a monoblastic cell line. Induction of B cell apoptosis by Mn2+ was time- and dose-dependent. The cell permeable tripeptide inhibitor of ICE family cysteine proteases, zVAD-fmk, suppressed Mn2+-induced apoptosis. Furthermore, Mn2+ triggered the activation of interleukin-1beta converting enzyme (ICE/caspase 1), followed by the activation of CPP32/Yama/Apopain/caspase-3. In addition, poly-(ADP-ribose) polymerase (PARP), a cellular substrate for CPP32 protease was degraded to generate apoptotic fragments in Mn2+-treated B cell lines. The inhibitor, zVAD-fmk suppressed Mn2+-triggered CPP32 activation and PARP cleavage and apoptosis. These results indicate that the activation of caspase family proteases is required for the apoptotic process induced by Mn2+ treatment of B cells. While the caspase-1 inhibitor YVAD was unable to block apoptosis, the caspase-3 specific inhibitor DEVD-cmk, partially inhibited Mn2+-induced CPP32 activation, PARP cleavage and apoptosis of cells. Moreover, Bcl-2 overexpression in BL-CL effectively protected cells from apoptosis and cell death induced by manganese. This is the first report showing the involvement of Mn2+ in the regulation of B lymphocyte death presumably via a caspase-dependent process with a death-protective effect of Bcl-2.
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PMID:Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. 1038 35

Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) followed by irradiation with visible light induces apoptosis in human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product has been shown to protect cells from a number of proapoptotic stimuli. In the present study, the influence of Bcl-2 overexpression on cellular resistance to photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP-ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD-MA (0-200 ng ml(-1)) and light. However, Bcl-2 overexpression was less effective at preventing cell death that occurred after photoactivation at high levels (50-100 ng ml(-1)) compared with lower doses (10-25 ng ml(-1)) of BPD-MA. These results indicate that caspase 3 and 6 activation and their regulation by Bcl-2 may play important roles in photodynamic therapy (PDT)-induced cell killing.
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PMID:Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy. 1040 99

TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c] quinolin-7-one dihydrochloride), a dual topoisomerase (topo) inhibitor, was developed as an anticancer agent by targeting topo I and topo II and has previously been shown to be effective against lung tumors. In this study, we investigated the cytotoxic activity of TAS-103 in various human cancer cell lines (including gastric, colon, squamous, lung, and breast cancer cells) and the induction of apoptosis by TAS-103. We next established stable transfectants of Bcl-2 in the gastric cancer cell line AZ521 and found that Bcl-2 blocked TAS-103-induced apoptosis. In addition, we demonstrated that the activities of ICE-like and CPP32-like proteases are involved in the signal transduction pathway of TAS-103-induced apoptosis. In summary, TAS-103 is a novel type of anticancer agent with a unique mechanism and could be useful as a lead compound for development of new drugs.
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PMID:A dual topoisomerase inhibitor, TAS-103, induces apoptosis in human cancer cells. 1042 63

The oncoprotein MDM2 binds and inactivates p53. MDM2 also binds to the tumor suppressor pRB, as well as E2F-1. E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed. To investigate the effect of adenovirus-mediated E2F-1 overexpression, MDM2-overexpressing tumor cell lines were treated by mock infection, infection with an adenoviral vector expressing beta galactosidase, or E2F-1 (Ad5CMV-E2F-1). Western blot analysis confirmed significant overexpression of E2F-1 in Ad5CMV-E2F-1-infected cells. E2F-1 overexpression resulted in marked growth inhibition and rapid loss of cell viability. Ad5CMV-E2F-1 infection resulted in early S phase entry, followed by apoptotic cell death. E2F-1 overexpression was associated with a marked decrease in MDM2 levels and no evidence of increased Bax levels, whereas p53 and Bcl-2 levels remained undetectable. Cleavage of poly-ADP-ribose polymerase and caspase 3/CPP32 implicated activation of the caspase cascade in E2F-1-mediated apoptosis. These results indicate that adenovirus-mediated E2F-1 overexpression in MDM2-overexpressing tumor cells results in decreased MDM2 expression and widespread apoptosis. Because MDM2-overexpressing tumors are often resistant to p53 gene therapy, adenovirus-mediated E2F-1 gene therapy may be a promising alternative strategy.
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PMID:Adenovirus-mediated E2F-1 gene transfer inhibits MDM2 expression and efficiently induces apoptosis in MDM2-overexpressing tumor cells. 1047 12

GRP94 is a 94-kDa chaperone glycoprotein with Ca(2+)-binding properties. We report here that during apoptosis induced by the topoisomerase II inhibitor etoposide, a fraction of GRP94 associated with the endoplasmic reticulum membrane undergoes specific proteolytic cleavage, coinciding with the activation of the caspase CPP32 and initiation of DNA fragmentation. In vivo, inhibitors of caspases able to block etoposide-induced apoptosis can only partially protect GRP94 from proteolytic cleavage, whereas complete inhibition is observed with calpain inhibitor I but not with the proteasome inhibitor. In vitro, GRP94 is not a substrate for CPP32; rather, it can be completely cleaved by calpain, a Ca(2+)-regulated protease. The cleavage of GRP94 by calpain is Ca(2+)-dependent and generates a discrete polypeptide of 80 kDa. In contrast, calpain has no effect on other stress proteins such as GRP78 or HSP70. Further, immunohistochemical staining reveals specific co-localization of GRP94 with calpain in the perinuclear region following etoposide treatment. We further showed that reduction of GRP94 by antisense decreased cell viability in etoposide-treated Jurkat cells. Our studies provide new evidence that the cytoprotective GRP94, as in the case of the antiapoptotic protein Bcl-2, can be targets of proteolytic cleavage themselves during the apoptotic process.
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PMID:The endoplasmic reticulum chaperone glycoprotein GRP94 with Ca(2+)-binding and antiapoptotic properties is a novel proteolytic target of calpain during etoposide-induced apoptosis. 1049 10

Glucocorticoids and fludarabine are able to induce typical features of apoptosis in CLL lymphocytes. Cysteinyl aspartate specific proteases (caspases) play a key biochemical role in the apoptotic pathway. Caspase activation following cytotoxic stimuli leads to highly specific proteolytic cleavage of functionally important cellular enzymes. One of them is poly ADP-ribose) polymerase (PARP). To some extent caspase activation seems to be under the control of the Bcl-2 family of interacting proteins. We determined the role of Bcl-2-family proteins Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), activation of caspase-3 (CPP32/Yama) and activation of PARP in CLL apoptosis. All 21 analyzed CLL samples expressed Bcl-2 and Bax. Four of 13 (31%) samples with a low Bcl-2/Bax ratio exhibited in vitro prednisolone resistance, whereas eight of nine (88%) samples with a high Bcl-2/Bax ratio were in vitro resistant (</=0.025). There was no significant correlation between clinical pre-treatment status and Bcl-2/Bax ratio. Caspase-3/CPP32 activity increase was registered after dexamethasone as well as after fludarabine treatment in CLL lymphocytes in vitro. Caspase inhibitor Z-VAD.fmk was only able to partially block dexamethasone-induced and spontaneous apoptosis but not fludarabine-induced apoptosis in CLL lymphocytes. PARP activity decreased after dexamethasone and fludarabine treatment. PARP inhibitor 3-aminobenzamide (3-AB) was able to partially inhibit dexamethasone-induced apoptosis but not fludarabine-induced and spontaneous apoptosis.
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PMID:Drug-induced apoptosis in chronic lymphocytic leukemia. 1055 65

A single intraperitoneal injection of 75 mg/kg N-methyl-N-nitrosourea (MNU) was given to 50-day-old female Sprague-Dawley rats and examined sequentially 12 and 24 hours, and 3 and 7 days after MNU treatment. Photoreceptor cell death was evoked in all treated rats. After MNU treatment, 7-methyldeoxyguanosine DNA adduct was detected selectively in photoreceptor cell nuclei at 12 hours, followed by photoreceptor cell apoptosis as confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling signals which peaked at 24 hours and continued until day 7 when several layers of photoreceptor cell nuclei were left. In apoptosis cascade, down-regulation of Bcl-2 was seen at 12 hours and up-regulation of Bax was seen at 24 hours, and caspase family (caspase 3/CPP32, caspase 6/Mch2, and caspase 8/FLICE protease) activities peaked 72 hours after MNU treatment. Therefore MNU-induced photoreceptor cell death was attributed to DNA adduct formation restricted to photoreceptor cell nuclei leading to photoreceptor cell apoptosis by up-regulation of Bax protein, down-modulation of Bcl-2 protein, and activation of caspases 3, 6, and 8.
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PMID:Mechanisms of photoreceptor cell apoptosis induced by N-methyl-N-nitrosourea in Sprague-Dawley rats. 1057 6

alpha-Fetoprotein (AFP) is an oncoembryonal protein with multiple cell growth regulating, differentiating and immunosuppressive activities. Previous studies have shown that treatment of tumor cells in vitro with 1-10 microM AFP produces significant suppression of tumor cell growth by inducing dose-dependent cytotoxicity, but the molecular mechanisms underlying these AFP functions are obscure. Here, we show that AFP cytotoxicity is closely related to apoptosis, as shown by cell morphology, nuclear DNA fragmentation and caspase-3-like activity resulting in cleavage of poly(ADP-ribose) polymerase. Apoptosis was significantly inhibited by a CPP32 family protease inhibitor whereas a general caspase inhibitor had no inhibitory effect, showing some enhancement of AFP-mediated cell death. Using fluorogenic caspase substrates, we found that caspase-3-like proteases were activated as early as 4 h after treatment of Raji cells with 15 microM AFP, whereas caspase-1, caspase-8, and caspase-9-like activity was not detected during the time interval 0.5-17 h. AFP treatment of Raji cells increased Bcl-2 protein, showing that AFP-induced apoptosis is not explained by downregulation of the Bcl-2 gene. This also suggests that AFP operates downstream of the Bcl-2-sensitive step. AFP notably decreased basal levels of soluble and membrane-bound Fas ligand. Incubation of AFP-sensitive tumor cells (HepG2, Raji) with neutralizing anti-Fas, anti-tumor necrosis factor receptor (TNFR)1 or anti-TNFR2 mAb did not prevent AFP-induced apoptosis, demonstrating its independence of Fas-dependent and TNFR-dependent signaling. In addition, it was found that cells resistant to TNF-induced (Raji) or Fas-induced (MCF-7) apoptosis are, nevertheless, sensitive to AFP-mediated cell death. In contrast, cells sensitive to Fas-mediated cell death (Jurkat) are completely resistant to AFP. Taken as a whole, our data demonstrate that: (a) AFP induces apoptosis in tumor cells independently of Fas/Fas ligand or TNFR/TNF signaling pathways, and (b) AFP-mediated cell death involves activation of the effector caspase-3-like proteases, but is independent of upstream activation of the initiator caspase-1, caspase-8, and caspase-9-like proteases.
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PMID:alpha-fetoprotein causes apoptosis in tumor cells via a pathway independent of CD95, TNFR1 and TNFR2 through activation of caspase-3-like proteases. 1058 68

Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is one of the most important chemotherapeutic agents; however, the mechanisms of resistance to this drug are still unknown. Recent reports have demonstrated that chemotherapy can induce apoptosis in some cancer cells, indicating that apoptosis may play a very important role in cancer therapy. Therefore, we used a CDDP-resistant cell line from the human epidermoid carcinoma cell line A431 to investigate whether the modulation of apoptosis influences CDDP resistance. In the CDDP-resistant cell, the cell cycle was not perturbed after CDDP treatment. DNA gel electrophoresis and ELISA of the CDDP-resistant cell showed reduced apoptosis when compared with A431 cells treated with CDDP. We determined the p53, Bcl-2, Bax and CPP32 protein levels by Western blotting. This analysis demonstrated a marked increase in Bcl-2 protein levels and a reduction in CPP32 protein levels in CDDP-resistant cells. Our results indicate that the reduction of apoptosis was one of the CDDP-resistant mechanisms, and that reduced apoptosis in CDDP-resistant cells was influenced by Bcl-2 and CPP32 proteins.
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PMID:Regulation of apoptosis reduction in the cisplatin-resistant A431 cell line by Bcl-2 and CPP32. 1060


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