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)

Arsenic trioxide (As(2)O(3)) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As(2)O(3) on solid tumors are poorly defined. Previously, we reported that As(2)O(3) induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As(2)O(3) treatment. When upregulation of BNIP3 induced by As(2)O(3) was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3 Delta TM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As(2)O(3)-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As(2)O(3)-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As(2)O(3) acts to induce autophagic cell death in malignant glioma cells.
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PMID:Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. 1559 27

Regulation of Purkinje cell (PC) number is critical for proper assembly and function of the cerebellum. Murine cerebellar neurogenesis yields supernumerary populations of cells that are subject to programmed cell death during development and aging. This study focuses on the control of mouse PC number during development and the consequences of interrupting normal cell death. Purkinje cell-specific regulatory elements from the pcp2 gene were employed to target expression of two anti-apoptotic proteins, human BCL-2 and adenovirus E1B 19k to the PCs of transgenic mice. Comparative morphometric analyses indicated no significant difference in PC numbers in the strongest BCL-2 expressing line, while a 14.2% increase was noted in the pcp2/E1B 19k transgenic line. The temporal transgene expression patterns of several mouse lines indicated that PC numbers are normally adjusted during the first postnatal week. Crossbreeding studies demonstrated that both Bcl-2 and E1B 19k transgenes provided Purkinje cell protection from SV40 Tag-induced cell death. Interestingly, RotaRod behavioral analysis demonstrated that 'rescued' Purkinje cells degrade cerebellar function. Furthermore, aged E1B 19k and Bcl-2 mice exhibited decreased RotaRod performance despite increased PC numbers. These findings have implications regarding neuronal death during development and aging as well as cellular and genetic strategies to circumvent neuronal degeneration.
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PMID:Enhanced Purkinje cell survival but compromised cerebellar function in targeted anti-apoptotic protein transgenic mice. 1591 45

In this report, we conducted a comprehensive survey of Bcl-2 family members, a divergent group of proteins that regulate programmed cell death by an evolutionarily conserved mechanism. Using comparative sequence analysis, we found novel sequences in mammals, nonmammalian vertebrates, and in a number of invertebrates. We then asked what conclusions could be drawn from phyletic distribution, intron/exon structures, sequence/structure relationships, and phylogenetic analyses within the updated Bcl-2 family. First, multidomain members having a sequence pattern consistent with the conservation of the Bcl-X(L)/Bax/Bid topology appear to be restricted to multicellular animals and may share a common ancestry. Next, BNip proteins, which were originally identified based on their ability to bind to E1B 19K/Bcl-2 proteins, form three independent monophyletic branches with different evolutionary history. Lastly, a set of Bcl-2 homology 3-only proteins with unrelated secondary structures seems to have evolved after the origin of Metazoa and exhibits diverse expansion after speciation during vertebrate evolution.
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PMID:Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators. 1609 67

We are currently conducting clinical trials of E1A gene therapy for patients with ovarian cancer. The adenovirus type 5 E1A gene suppresses growth of ovarian cancer cells that overexpress HER-2/neu (HER2) and growth of some--but not all--that express low HER2. In HER2-overexpressing cells, suppression by E1A is predominantly by down-regulation of HER2, but the mechanism in low HER2-expressing cells is not fully understood. The adenoviral E1B protein has sequential and functional homology to Bcl-2 and prolongs the viability of adenovirus host cells by inhibiting E1A-induced apoptosis. Bcl-2 is overexpressed in ovarian cancer and participates in chemoresistance; we hypothesized that Bcl-2 inhibits E1A-induced apoptosis leading to resistance to E1A gene therapy. E1A suppressed colony formation of ovarian cancer cells that express low levels of Bcl-2 and HER2 (OVCAR-3 and OVCA 433), but enhanced colony formation in low HER2-, high Bcl-2-expressing ovarian cancer cells (2774 and HEY). Treating 2774 or HEY cells with antisense oligonucleotide Bcl-2 (Bcl-2-ASO) did not reduce cell viability. E1A combined with Bcl-2-ASO led to significant decreases in cell viability resulting from increased apoptosis relative to cells treated with E1A alone (P < 0.05). The increase in apoptosis was partly due to cytochrome c release and subsequently caspase-9 activation by Bcl-2-ASO. Finally, in an ovarian cancer xenograft model, treatment with Bcl-2-ASO did not prolong survival, but E1A plus Bcl-2-ASO did (P < 0.001). In conclusion, ovarian tumors overexpressing Bcl-2 may not respond well to E1A gene therapy, but treatment with a combination of E1A and Bcl-2-ASO may overcome this resistance.
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PMID:Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapy in a low HER2-expressing ovarian cancer xenograft model. 1616 19

The mouse breast cancer cell lines 4T1, 4T07, and 67NR are highly tumorigenic but vary in metastatic potential: 4T1 widely disseminates, resulting in secondary tumors in the lung, liver, bone, and brain; 4T07 spreads to the lung and liver but is unable to establish metastatic nodules; 67NR is unable to metastasize. The Bcl-2/adenovirus E1B 19 kDa interacting protein-3 (Bnip-3) was recently shown to be absent after hypoxia in pancreatic cancer cell lines whereas its overexpression restored hypoxia-induced cell death. We found that Bnip-3 expression increased after 6 hours of hypoxia in all cell lines tested but was highest in the nonmetastatic 67NR cells and lowest in the highly metastatic 4T1 cells. Hypoxia-induced expression of Bnip-3 in the disseminating but nonmetastatic 4T07 cells was intermediate compared with 4T1 and 67NR cells. Cleaved caspase-3, a key downstream effector of cell death, increased after 6 hours of hypoxia in the 67NR and 4T07 cells by 1.9- and 2.5-fold, respectively. Conversely, cleaved caspase-3 decreased by 45% in the highly metastatic 4T1 cells after hypoxia. Small interfering RNA oligonucleotides targeting endogenous Bnip-3 blocked cell death and increased clonigenic survival after hypoxic challenge in vitro and increased primary tumor size and enabled metastasis to the lung, liver, and sternum of mice inoculated with 4T07 cells in vivo. These data inversely correlate the hypoxia-induced expression of the cell death protein Bnip-3 to metastatic potential and suggest that loss of Bnip-3 expression is critical for malignant and metastatic evasion of hypoxia-induced cell death.
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PMID:Bcl-2/adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver, and bone. 1635 80

Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a mitochondrial pro-apoptotic protein that has a single Bcl-2 homology 3 (BH3) domain and a COOH-terminal transmembrane (TM) domain. Al-though it belongs to the Bcl-2 family and can hetero-dimerize with Bcl-2, its pro-apoptotic activity is distinct from those of other members of the Bcl-2 family. For example, cell death mediated by BNIP3 is independent of caspases and shows several characteristics of necrosis. Furthermore, the TM domain, but not the BH3 domain, is required for dimerization, mitochondrial targeting and pro-apoptotic activity. BNIP3 plays an important role in hypoxia-induced death of normal and malignant cells. Its expression is markedly increased in the hypoxic regions of some solid tumors and appears to be regulated by hypoxia-inducible fac-tor (HIF), which binds to a site on the BNIP3 promoter. Silencing, followed by methylation, of the BNIP3 gene occurs in a significant proportion of can-cer cases, especially in pancreatic cancers. BNIP3 also has a role in the death of cardiac myocytes in ischemia. Further studies of BNIP3 should provide insight into hypoxic cell death and may contribute to im-proved treatment of cancers and cardiovascular diseases.
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PMID:Regulation of BNIP3 in normal and cancer cells. 1651 41

Manganese superoxide dismutase (MnSOD) is a latent tumor suppressor gene. To investigate the therapeutic effect of MnSOD and its mechanisms, a replication-competent recombinant adenovirus with E1B 55-kDa gene deletion (ZD55) was constructed, and human MnSOD and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes were inserted to form ZD55-MnSOD and ZD55-TRAIL. ZD55-MnSOD exhibited an inhibition in tumor cell growth approximately 1,000-fold greater than Ad-MnSOD. ZD55-TRAIL was shown to induce the MnSOD expression in SW620 cells. Accordingly, by the combined use of ZD55-MnSOD with ZD55-TRAIL (i.e., "dual gene virotherapy"), all established colorectal tumor xenografts were completely eliminated in nude mice. The evidence exists that the MnSOD overexpression led to a slower tumor cell growth both in vitro and in vivo as a result of apoptosis caused by MnSOD and TRAIL overexpression after adenoviral transduction. Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome c. Cytochrome c finally triggered apoptosis by activating caspase-9 and caspase-3 in apoptotic cascade. Bax-mediated apoptosis seems to be dependent on caspase-8 activation because the inhibition of caspase-8 prevented Bid processing and Bax translocation. In conclusion, our dual gene virotherapy completely eliminated colorectal tumor xenografts via enhanced apoptosis, and this novel strategy points toward a new direction of cancer treatment.
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PMID:Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. 1661 54

Hypoxia plays a major role in the malignant progression of tumors. Here, we investigate the expression of Bcl-2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), a proapoptotic Bcl-2 family member, and its relationship to hypoxia in cervical cancer cell lines and clinical samples of cervical cancer. Cervical cancer cell lines were grown under hypoxia or normoxia, and BNIP3 mRNA expression was examined by Northern blot analysis. In 50 patients with cervical cancer, intratumoral oxygen measurement with the Eppendorf electrode and needle biopsies of the tumor were performed. The obtained tissue was subsequently analyzed by immunohistochemistry with an anti-BNIP3 antibody. Cervical cancer tissue collected upon surgery was used for Northern blot analysis of in vivo BNIP3 mRNA expression. BNIP3 mRNA is strongly induced under hypoxic conditions in all cervical cancer cell lines investigated. Furthermore, Northern blot analysis revealed that BNIP3 mRNA is expressed in cervical cancer tissue. Using immunohistochemistry, we demonstrated that BNIP3 protein is expressed in 82% of the investigated cervical cancers and that more advanced tumor stages showed significantly stronger BNIP3 expression. However, we observed no correlation between BNIP3 expression and intratumoral hypoxia. In conclusion, BNIP3 is expressed in different cervical cancer cell lines as well as in clinical samples of cervical cancer. Although BNIP3 is clearly hypoxia-inducible in vitro, our results suggest additional mechanisms of BNIP3 regulation in vivo. Our findings therefore highlight a discrepancy between in vitro models of tumor hypoxia and the complexity of human cancer.
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PMID:Hypoxia and expression of the proapoptotic regulator BNIP3 in cervical cancer. 1680 23

Nitric oxide (NO) produced by NO synthases causes nitration and nitrosylation of cellular factors. We have shown previously that endogenously produced or exogenously added NO induces expression of BNIP3 (Bcl-2/adenovirus E1B 19 kDa-interacting protein 3), leading to death of macrophages (Yook, Y.-H., Kang, K.-H., Maeng, O., Kim, T.-R., Lee, J.-O., Kang, K.-i., Kim, Y.-S., Paik, S.-G., and Lee, H. (2004) Biochem. Biophys. Res. Commun. 321, 298-305). We now provide evidence that Ras mediates NO-induced BNIP3 expression via the MEK/ERK/hypoxia-inducible factor (HIF)-1 pathway. (a) ras-Q61L, a constitutively active form of Ras, up-regulated BNIP3 protein expression by enhancing Bnip3 promoter activity, and ras-S17N, a dominant-negative form, and ras-C118S, an S-nitrosylation mutant, blocked NO-induced BNIP3 expression, suggesting that Ras acts downstream of NO and that NO activates Ras by nitrosylation. (b) U0126, a specific MEK inhibitor, completely abolished BNIP3 expression and the stimulation of promoter activity by NO and Ras, whereas 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, SB203580, and wortmannin, specific inhibitors of soluble guanylyl cyclase, p38 MAPK, and phosphatidylinositol 3-kinase, respectively, had no effect. Ras, MEK1/2, and ERK1/2 were sequentially activated by NO treatment of macrophages. (c) Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction, and HIF-1alpha was strongly induced by NO. (d) Transient expression of activated Ras promoted macrophage death, as did NO, and this Ras-mediated cell death was inhibited by silencing BNIP3 expression. These results suggest that NO-induced death of macrophages is mediated, at least in part, by BNIP3 induction.
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PMID:Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric oxide-induced cell death. 1695 13

Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug- or tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis and that Hif-1alpha plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1alpha by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1alpha-dependent manner. As GLUT-1 was induced via Hif-1alpha under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1alpha-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.
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PMID:Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. 1704 58


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