Effects of physiological and synthetic IAP antagonism on c-IAP dependent signaling

ABSTRACT: Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) play central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-kB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. Additionally, 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. This submission contains two different experiments. In experiment 1, cells were exposed to drug treament (DMSO or SM-164) for 3 hours. In experiment 2, cells were exposed to an adherent layer of CHO cells either expressing or not CD30L. Each treatment in each experiment was conducted once, leading to a total of 4 samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Mats Ljungman 

PROVIDER: E-GEOD-64927 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress