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)

Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1-100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G2-M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-kappaB (NF-kappaB) via IkappaB degradation through IkappaB kinase (IKKalpha and IKKbeta) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKKalpha and beta did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced beta-tubulin polymerization and the formation of p50/beta-tubulin complex. However, beta-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKKalpha and beta. Moreover, epothilone B and D increased the expressions of NF-kappaB-dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B-induced cell death and NF-kappaB activation. These findings suggest that the activation of NF-kappaB/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization-independent manner.
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PMID:Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factor-kappaB/IkappaB kinase signal pathway. 1793 70

The costimulatory molecule OX40 (CD134) is required in many instances for effective T cell-mediated immunity, controlling proliferation, and survival of T cells after encountering specific Ag. We previously found that the functional targets of OX40 are survivin and aurora B that regulate proliferation and Bcl-2 antiapoptotic family members that regulate survival. However, the intracellular pathways from OX40 that mediate these effects are unclear. In this study, we show that OX40 signaling can target the canonical NF-kappaB (NF-kappaB1) pathway in peripheral Ag-responding CD4 T cells. Phosphorylation of IkappaBalpha, nuclear translocation of NF-kappaB1/p50 and RelA, and NF-kappaB1 activity, are impaired in OX40-deficient T cells. Retroviral transduction of active IkappaB kinase that constitutively activates NF-kappaB1 rescues the poor expansion and survival of OX40-deficient T cells, directly correlating with increased expression and activity of survivin, aurora B, and Bcl-2 family members. Moreover, active IkappaB kinase expression alone is sufficient to restore the defective expansion and survival of OX40-deficient T cells in vivo when responding to Ag. Thus, OX40 signals regulate T cell number and viability through the NF-kappaB1 pathway that controls expression and activity of intracellular targets for proliferation and survival.
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PMID:Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. 1849 Jul 23

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced apoptosis in human breast MCF-7 cancer cells was confirmed by sub-G1 formation, phosphatidylserine (PS) externalization, and poly (ADP-ribose) polymerase (PARP) cleavage with an IC50 of 2 microg/ml at 48 h. Effects of CTX III on proliferation and apoptosis correlated with upregulation of Bax, and downregulation of Bcl-XL, Bcl-2, and XIAP, with no appreciable alteration on the protein levels of Bid, Bim, and survivin. CTX III treatment also caused release of mitochondrial cytochrome c to the cytosol, which led to subsequent activation of capase-9. Moreover, CTX III inhibited the nuclear factor-kappaB (NF-kappaB) activation through inhibition of IkappaB kinase (IkappaK) activity. Overall, our results indicate that CTX III downregulates NF-kappaB in MCF-7 cells, leading to the suppression of proliferation and induction of apoptosis. These findings suggest the molecular basis for CTX III-induced apoptotic death of MCF-7 cells.
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PMID:Effects of cardiotoxin III on NF-kappaB function, proliferation, and apoptosis in human breast MCF-7 cancer cells. 1940 76

By genetically ablating IkappaB kinase (IKK)-mediated activation of the transcription factor NF-kappaB in the B cell lineage and by analyzing a mouse mutant in which immunoglobulin lambda-chain-positive B cells are generated in the absence of rearrangements in the locus encoding immunoglobulin kappa-chain, we define here two distinct, consecutive phases of early B cell development that differ in their dependence on IKK-mediated NF-kappaB signaling. During the first phase, in which NF-kappaB signaling is dispensable, predominantly kappa-chain-positive B cells are generated, which undergo efficient receptor editing. In the second phase, predominantly lambda-chain-positive B cells are generated whose development is ontogenetically timed to occur after rearrangements of the locus encoding kappa-chain. This second phase of development is dependent on NF-kappaB signals, which can be substituted by transgenic expression of the prosurvival factor Bcl-2.
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PMID:Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. 1941 80

The antiapoptotic Bcl-2 family member Bfl-1 is up-regulated in many human tumors in which nuclear factor-kappaB (NF-kappaB) is implicated and contributes significantly to tumor cell survival and chemoresistance. We previously found that NF-kappaB induces transcription of bfl-1 and that the Bfl-1 protein is also regulated by ubiquitin-mediated proteasomal degradation. However, the role that dysregulation of Bfl-1 turnover plays in cancer is not known. Here we show that ubiquitination-resistant mutants of Bfl-1 display increased stability and greatly accelerated tumor formation in a mouse model of leukemia/lymphoma. We also show that tyrosine kinase Lck is up-regulated and activated in these tumors and leads to activation of the IkappaB kinase, Akt, and extracellular signal-regulated protein kinase signaling pathways, which are key mediators in cancer. Coexpression of Bfl-1 and constitutively active Lck promoted tumor formation, whereas Lck knockdown in tumor-derived cells suppressed leukemia/lymphomagenesis. These data demonstrate that ubiquitination is a critical tumor suppression mechanism regulating Bfl-1 function and suggest that mutations in bfl-1 or in the signaling pathways that control its ubiquitination may predispose one to cancer. Furthermore, because bfl-1 is up-regulated in many human hematopoietic tumors, this finding suggests that strategies to promote Bfl-1 ubiquitination may improve therapy.
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PMID:Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. 2018 81

Anticancer effects of beta-lapachone (beta-lap) are due to generation of ROS and metabolic catastrophes as a result of NAD(P)H:quinone oxidoreductase (NQO1)-mediated futile cycling between the oxidized and reduced forms of beta-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-kappaB and that beta-lap suppresses the TNF-induced NF-kappaB activation. We investigated whether or not NQO1 is involved and beta-lap suppresses the radiation-induced NF-kappaB activation using A549 human lung cancer cells and NQO1-knock down A549 cells (shNQO1 A549 cells). Irradiation with 4 Gy markedly increased the DNA binding activity of NF-kappaB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-kappaB activation. Treatment with 10 micronM beta-lap for 4 h almost completely abrogated the radiation-induced increase in NF-kappaB activation and the transcription of NF-kappaB target genes such as bcl2, gadd45beta and cyclinD1. Moreover, beta-lap markedly suppressed the activation of IkappaB kinase gamma (IKKgamma) and the subsequent phosphorylation of IkappaBalpha, thereby inhibiting NF-kappaB activation. It is concluded that beta-lap suppresses the radiation-induced activation of NF-kappaB by interrupting the involvement of NQO1 in the activation of NF-kappaB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by beta-lap may, in part, be attributed to beta-lap-induced suppression of NF-kappaB activation.
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PMID:Beta-lapachone suppresses radiation-induced activation of nuclear factor-kappaB. 2020 Apr 74


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