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      MAP kinase-dependent, NF-kappaB-independent regulation of inhibitor of apoptosis protein genes by TNF-alpha.

      Journal of Cellular Physiology

      Apoptosis, physiology, Cell Line, Cell Survival, Dactinomycin, pharmacology, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Humans, Inhibitor of Apoptosis Proteins, genetics, metabolism, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinases, NF-kappa B, Nucleic Acid Synthesis Inhibitors, RNA, Messenger, Transcription Factor AP-1, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases

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          The inhibitor of apoptosis protein (IAP) family of molecules regulates apoptotic processes triggered by various stimuli. However, the mechanisms involved in the regulation of the IAP genes are not fully understood. In this report, we examined roles of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases in tumor necrosis factor-alpha (TNF-alpha)-induced expression of IAP genes. In human endothelial cells, TNF-alpha induced c-IAP1 and c-IAP2, but not XIAP and TIAP/Survivin, at the transcriptional level. Inactivation of NF-kappaB by overexpression of a super-repressor mutant of IkappaBalpha did not affect the induction of IAPs by TNF-alpha. In contrast, extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase were activated after stimulation with TNF-alpha, and inhibition of each kinase by PD098059, SB203580, curcumin, or SP600125 substantially attenuated the TNF-alpha-induced c-IAP1 and c-IAP2 expression. To examine whether the MAP kinases-mediated induction of IAPs contributes to survival of TNF-alpha-exposed cells, cells were pretreated with MAP kinase inhibitors and stimulated with TNF-alpha. Treatment with kinase inhibitors alone did not induce apoptosis but enhanced markedly TNF-alpha-triggered apoptosis. Furthermore, overexpression of either c-IAP1 or c-IAP2 diminished the apoptosis-promoting effects of MAP kinase inhibitors. These data indicated that TNF-alpha induced expression of c-IAP1 and c-IAP2 via MAP kinases, but not via NF-kappaB, and that MAP kinases participated in the inhibition of apoptosis by induction of c-IAPs in TNF-alpha-stimulated endothelial cells. Copyright 2006 Wiley-Liss, Inc.

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