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)

We have identified Nix, a homolog of the E1B 19K/Bcl-2 binding and pro-apoptotic protein Nip3. Human and murine Nix have a 56 and 53% amino acid identity to human and murine Nip3, respectively. The carboxyl terminus of Nix, including a transmembrane domain, is highly homologous to Nip3 but it bears a longer and distinct asparagine/proline-rich N terminus. Human Nip3 maps to chromosome 14q11.2-q12, whereas Nix/BNip3L was found on 8q21. Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. Following transfection, Nix protein undergoes progressive proteolysis to an 11-kDa C-terminal fragment, which is blocked by the proteasome inhibitor lactacystin. Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. Nix can overcome the suppressers Bcl-2 and Bcl-XL, although high levels of Bcl-XL expression will inhibit apoptosis. We propose that Nix and Nip3 form a new subfamily of pro-apoptotic mitochondrial proteins.
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PMID:Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. 986 3

The Bcl-2 homologous region 3 (BH3) is sufficient for interaction of pro-apoptotic with anti-apoptotic Bcl-2 family members, and functional antagonism may determine whether cell survival or death is the outcome of this protein-protein interaction. To address the biological role of BH3, two Bax-Bcl2 chimeras were generated in which 13 amino acids encompassing BH3 was swapped between anti-apoptotic Bcl-2 and pro-apoptotic Bax, thereby generating Bax with BH3 of Bcl-2 (Bax-BH3Bcl2), and Bcl-2 with BH3 of Bax (Bcl2-BH3Bax). Function and binding of the chimeras was then assessed utilizing the adenoviral Bcl-2 homologue, E1B 19K, which blocks apoptosis, and interacts with Bax, but not with Bcl-2. E1B 19K did not interact with Bax-BH3Bcl2 but did interact with Bcl2-BH3Bax. Bax-BH3Bcl2 retained pro-apoptotic function, while Bcl2-BH3Bax did not exhibit either pro- or anti-apoptotic activity. Thus, BH3 of Bcl-2 encodes binding specificity but not the apoptotic propensity. E1B 19K could not block Bax-BH3Bcl2-induced apoptosis, suggesting that E1B 19K may act to antagonize pro-apoptotic proteins rather than as an effector of survival. Furthermore, Bax expression disrupted the mitochondrial membrane potential, which could be rescued by E1B 19K expression. Thus, BH3 controls the binding specificity among Bcl-2 family members, and direct interaction between pro-apoptotic and anti-apoptotic proteins is a mechanism to regulate mitochondrial membrane potential and apoptosis.
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PMID:Interaction of E1B 19K with Bax is required to block Bax-induced loss of mitochondrial membrane potential and apoptosis. 988 1

Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. This study shows that hydrogen peroxide-induced apoptosis in T-cells did not require tyrosine kinase p561ck, phosphatase CD45, the CD95 receptor and its associated Caspase-8. H2O2-triggered cell death led to the induced cleavage and activation of Caspase-3. Hydrogen peroxide-treatment of T-cells resulted in the formation of mitochondrial permeability transition pores, a rapid decrease of the mitochondrial transmembrane potential delta psi(m) and the release of Cytochrome C. Inhibition of the mitochondrial permeability transition by bongkrekic acid (BA), or interference with the mitochondrial electron transport system by rotenone or menadione prevented the cytotoxic effect of H2O2. Antimycin A, a mitochondrial inhibitor that increases the release of mitochondrial ROS (MiROS), enhanced apoptosis. Overexpression of Bcl-2 and the viral anti-apoptotic proteins BHRF-1 and E1B 19K counteracted H2O2-induced apoptosis. Pharmacological and genetic inhibition of transcription factor NF-kappaB protected cells from hydrogen peroxide-elicited cell death. This detrimental effect of NF-kappaB mediating hydrogen peroxide-induced cell death presumably relies on the induced expression of death effector genes such as p53, which was NF-kappaB-dependently upregulated in the presence of H2O2.
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PMID:Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB. 998 25

The adenovirus E1B 19,000-molecular-weight (19K) protein is a potent inhibitor of apoptosis and cooperates with E1A to transform primary rodent cells. E1B 19K shows sequence and functional homology to the mammalian antiapoptotic gene product, Bcl-2. Like Bcl-2, the biochemical mechanism of E1B 19K function includes binding to and antagonization of cellular proapoptotic proteins such as Bax, Bak, and Nbk/Bik. In addition, there is evidence that E1B 19K can affect gene expression, but whether this contributes to its antiapoptotic function has not been determined. In an effort to further understand the functions of E1B 19K, we screened for 19K-associated proteins by the yeast two-hybrid system. A novel protein, Btf (Bcl-2-associated transcription factor), that interacts with E1B 19K as well as with the antiapoptotic family members Bcl-2 and Bcl-xL but not with the proapoptotic protein Bax was identified. btf is a widely expressed gene that encodes a protein with homology to the basic zipper (bZip) and Myb DNA binding domains. Btf binds DNA in vitro and represses transcription in reporter assays. E1B 19K, Bcl-2, and Bcl-xL sequester Btf in the cytoplasm and block its transcriptional repression activity. Expression of Btf also inhibited transformation by E1A with either E1B 19K or mutant p53, suggesting a role in either promotion of apoptosis or cell cycle arrest. Indeed, the sustained overexpression of Btf in HeLa cells induced apoptosis, which was inhibited by E1B 19K. Furthermore, the chromosomal localization of btf (6q22-23) maps to a region that is deleted in some cancers, consistent with a role for Btf in tumor suppression. Thus, btf may represent a novel tumor suppressor gene residing in a unique pathway by which the Bcl-2 family can regulate apoptosis.
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PMID:Btf, a novel death-promoting transcriptional repressor that interacts with Bcl-2-related proteins. 1033 Jan 79

The Bcl-2 family of proteins regulates apoptosis, the cell death program triggered by activation of certain proteases (caspases). An attractive model for how Bcl-2 and its closest relatives prevent caspase activation is that they bind to and inactivate an adaptor protein required for procaspase processing. That model has been supported by reports that mammalian prosurvival Bcl-2 relatives bind the adaptor Apaf-1, which activates procaspase-9. However, the in vivo association studies reported here with both overexpressed and endogenous Apaf-1 challenge this notion. Apaf-1 could be immunoprecipitated together with procaspase-9, and the Apaf-1 caspase-recruitment domain was necessary and sufficient for their interaction. Apaf-1 did not bind, however, to any of the six known mammalian prosurvival family members (Bcl-2, Bcl-x(L), Bcl-w, A1, Mcl-1, or Boo), or their viral homologs adenovirus E1B 19K and Epstein-Barr virus BHRF-1. Endogenous Apaf-1 also failed to coimmunoprecipitate with endogenous Bcl-2 or Bcl-x(L), or with two proapoptotic relatives (Bax and Bim). Moreover, apoptotic stimuli did not induce Apaf-1 to bind to these family members. Thus, the prosurvival Bcl-2 homologs do not appear to act by sequestering Apaf-1 and probably instead constrain its activity indirectly.
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PMID:Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. 1044 54

We have previously reported on cloning of the human gene encoding Bcl-2/adenovirus E1B 19 kDa-interacting protein 3-like protein (Bnip3L) and its growth inhibitory effect on cancer cells. Here we show that Bnip3L contains a motif similar to the BH3 domain which is conserved in Bcl-2 family proteins as well as containing a membrane-anchoring domain, and that Bnip3L interacts with Bcl-2 and Bcl-xL. Immunofluorescence microscopy revealed that Bnip3L was localized in the mitochondria, when in the presence of the membrane-anchoring domain. Transient expression of Bnip3L induced apoptosis of Rat-1 and HeLa cells and mutational analysis revealed that the BH3 domain and the membrane-anchoring domain were required for Bnip3L to induce cell death. Addition of recombinant Bnip3L to isolated mitochondria induced membrane potential loss and cytochrome c release both of which have been suggested to be prerequisite for apoptotic cell death. These results suggest that Bnip3L is one of the BH3-containing pro-apoptotic proteins and that it targets the mitochondria when inducing apoptosis.
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PMID:Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability. 1046 96

E1A oncogene expression sensitizes mammalian cells to apoptosis triggered by cytolytic lymphocytes (CL) [16]. Most studies suggest that E1A-induced apoptosis involves a p53-dependent cellular pathway that is blocked by the E1B 19 kDa gene product. In this study, the roles of p53 and E1B 19 kDa were tested for E1A sensitization to CL-induced apoptosis in contrast with apoptosis triggered by TNF alpha or chemical injuries. E1A sensitization to immune-mediated (CL- or TNF-induced) apoptosis was independent of p53 expression and was resistant to blockade by E1B 19 kDa protein in mouse and hamster cells. In contrast, the p53 requirement for chemically induced apoptosis of E1A-sensitized cells varied with the agent used to treat cells. Apoptosis induced by diverse chemical agents (hygromycin, beauvericin, etoposide, H(2)O(2)) was blocked by E1B 19 kDa expression. Therefore, both the p53-dependence and the E1B 19 kDa blockade of E1A-induced cellular sensitization to apoptotic injury depend on the type of proapoptotic injury tested. These data suggest that the mechanisms by which E1A sensitizes tumor cells to immune-mediated apoptosis and to rejection by immunocompetent animals do not require cellular expression of wild-type p53 and can function independently of the Bcl-2-like, antiapoptotic mechanisms of E1B 19 kDa.
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PMID:E1A oncogene-induced cellular sensitization to immune-mediated apoptosis is independent of p53 and resistant to blockade by E1B 19 kDa protein. 1050 12

The signaling pathway leading to TGF-beta1-induced apoptosis was investigated using a TGF-beta1-sensitive hepatoma cell line, FaO. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease of the cell population in the G(1) phase concomitant with a slight increase of the cell population in the G(2)/M phase in response to TGF-beta1. TGF-beta1 induced a transient increase in the expression of Cdc2, cyclin A, cyclin B, and cyclin D1 at an early phase of apoptosis. During TGF-beta1-induced apoptosis, the transient increase in cyclin-dependent kinase (Cdk) activities coincides with a dramatic increase in the hyperphosphorylated forms of RB. Treatment with roscovitine or olomoucine, inhibitors of Cdc2 and Cdk2, blocked TGF-beta1-induced apoptosis by inhibiting RB phosphorylation. Overexpression of Bcl-2 or adenovirus E1B 19K suppressed TGF-beta1-induced apoptosis by blocking the induction of Cdc2 mRNA and the subsequent activation of Cdc2 kinase, whereas activation of Cdk2 was not affected, suggesting that Cdc2 plays a more critical role in TGF-beta1-induced apoptosis. In conclusion, we present the evidence that Cdc2 and Cdk2 kinase activity transiently induced by TGF-beta1 phosphorylates RB as a physiological target in FaO cells and that RB hyperphosphorylation may trigger abrupt cell cycle progression, leading to irreversible cell death.
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PMID:Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells. 1054 99

Fibroblast growth factor (FGF) receptor tyrosine kinases are involved in the regulation of cell growth, development, and differentiation in a variety of tissues. To isolate potential signaling molecules in the FGF signaling pathway, we have initiated a yeast two-hybrid screening using the cytosolic domain of FGF receptor-1 (Flg). Here we report the identification of BNIP-2, a previously cloned Bcl-2- and adenovirus E1B-associated protein, as a putative substrate of the receptor. When cotransfected in 293T cells, BNIP-2 was tyrosine-phosphorylated via Flg, but their interaction was transient and could only be seen by "capture" experiments with catalytically inert kinase mutants. When responsive cells were challenged with basic FGF, endogenous tyrosine-phosphorylated BNIP-2 could be precipitated with a BNIP-2 antibody. In addition, the recombinant BNIP-2 expressed in bacteria could be phosphorylated by active Flg in vitro. BNIP-2 shares a region of homology with the noncatalytic domain of Cdc42GAP, a GTPase-activating protein for the small GTP-binding molecule, Cdc42. We show here that BNIP-2 and Cdc42GAP could directly bind to each other and they also compete for the binding to the same target, Cdc42. Unexpectedly, BNIP-2, either produced as a bacterial recombinant protein or expressed in 293T cells, could stimulate the intrinsic GTPase activity of Cdc42. In all cases, tyrosine phosphorylation of BNIP-2 severely impaired its association with Cdc42GAP and its induced GTPase-activating protein-like activity toward Cdc42. These findings should allow us to further characterize the integration of signaling between receptor tyrosine kinases, GTP-binding molecules, and apoptotic pathways.
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PMID:Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. 1055 83

Epidemiology shows a clear correlation between chronic infection with the hepatitis B virus (HBV) and development of hepatocellular carcinoma (HCC). The potential role of the transactivating hepatitis B virus X protein (HBx) in transformation by HBV is controversial. Here we report that HBx suppresses transformation of primary rat embryo fibroblasts (REFs). Cooperating oncogenes like c-Ha-ras and c-myc transform REF very efficiently but cotransfection with HBx suppressed transformation of REFs down to 5%. Similarly, transfection of HBx together with the cooperating oncogenes Ha-ras and SV40 LTAg or c-Ha-ras and mutant p53 reduced the number of foci to 13%. Comparable results were obtained with HBx in the context of the whole HBV. Suppression of focus formation in REF could be partly relieved by cotransfection of apoptosis inhibitors Bcl-2 or E1B. However, cotransfection of apoptosis inhibitors crmA and p35 did not influence the proapoptotic functions of HBx. Thus, HBx may specifically activate the Bcl-2 sensitive pathway leading to apoptosis. Experiments with 13 HBx linker scanning mutants revealed that the domains necessary for HBx dependent transactivation overlap with the domains needed for the apoptotic/growth arrest functions of HBx.
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PMID:Induction of apoptosis by the transactivating domains of the hepatitis B virus X gene leads to suppression of oncogenic transformation of primary rat embryo fibroblasts. 1071 5


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