Abstract 2068: A genome-wide siRNA screen reveals various modulators of the IRE1-XBP-1 signaling branch of the unfolded protein response

Abstract

Abstract The unfolded protein response (UPR) is an essential cellular mechanism orchestrating endoplasmic reticulum (ER) homeostasis under various cytotoxic stresses. Dysregulation of the UPR signaling pathways is linked to multiple human diseases, including cancer. The inositol requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP-1) pathway is the most evolutionarily conserved signaling branch of the UPR. When activated, the endoribonuclease activity of the IRE1 cleaves the XBP-1 mRNA and generates a spliced form of XBP-1 which transcriptionally regulates cell metabolism, proliferation, survival and apoptosis. Here, we employed a genome-wide siRNA screen to systematically identify genes modulating the IRE1-XBP-1 signaling pathway of the UPR. We induced cellular ER stress with bortezomib, a proteasome inhibitor, and monitored the expression of XBP-1-luciferase fusion protein in which luciferase is fused in-frame with the spliced form of XBP-1. We identified over 100 of genes whose downregulation results in inhibition of bortezomib-induced XBP-1 splicing. These genes include diverse subsets of proteins that are involved in mRNA processing, transcription, cell cycle regulation and cell proliferation and differentiation. Furthermore, the screen reveals a connection of several oncogenes and tumor suppressors, such as Myc, Akt and cyclin K, to the UPR, underlining the important role of the IRE1-XBP-1 signaling branch in human cancers. In summary, our data suggest that the UPR is tightly connected with previously unappreciated pathways regulating various cellular processes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2068. doi:10.1158/1538-7445.AM2011-2068