title: Effects of physiological and synthetic IAP antagonism on c-IAP-dependent signaling.
abstract: Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) have central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-κB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. In addition, a number of synthetic compounds have been developed that also target the c-IAPs and induce their degradation. However, the extent of a synthetic IAP antagonist's ability to mirror the transcriptional program by a physiological signal remains unclear. Here we take a systems approach to compare the transcriptional programs triggered by activation of CD30, a well-characterized receptor previously shown to induce the degradation of the c-IAPs, to SM-164, a synthetic IAP antagonist that specifically triggers c-IAP degradation. Employing a technique that allows the specific analysis of newly transcribed RNA, we have generated comparative transcriptome profiles for CD30 activation and SM-164 treatment. Analysis of these profiles revealed that the genes regulated by each stimulus were not completely shared, indicating novel functions of IAP antagonists and consequences of c-IAP1/2 degradation. The data identified a role for c-IAP1/2 in the regulation of the ribosome and protein synthesis, which was subsequently confirmed by biological assays. These findings expand our knowledge of the roles of c-IAP1/2 in signaling and provide insight into the mechanism of synthetic IAP antagonists, furthering our understanding of their therapeutic potential.
authors: Graduate Program in Immunology, The University of Michigan, Ann Arbor, MI, USA.|Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.
authors: A J
authors: AJ
authors: Kocab
authors: Department of Radiation Oncology, The University of Michigan, Ann Arbor, MI, USA.|Bioinformatics Program, Department of Computational Medicine and Bioinformatics, The University of Michigan, Ann Arbor, MI, USA.
authors: A
authors: A
authors: Veloso
authors: Department of Radiation Oncology, The University of Michigan, Ann Arbor, MI, USA.
authors: M T
authors: MT
authors: Paulsen
authors: Department of Radiation Oncology, The University of Michigan, Ann Arbor, MI, USA.|Department of Environmental Health Sciences, School of Public Health, The University of Michigan, Ann Arbor, MI, USA.
authors: M
authors: M
authors: Ljungman
authors: Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.|Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, USA.
authors: C S
authors: CS
authors: Duckett
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003412:Cricetulus; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D017730:Ki-1 Antigen / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D051034:Inhibitor of Apoptosis Proteins; D017730:Ki-1 Antigen; D016328:NF-kappa B; C533467:SM 164; D014230:Triazoles