The Internal Ribosome Entry Site-Mediated Translation of Antiapoptotic Protein XIAP Is Modulated by the Heterogeneous Nuclear Ribonucleoproteins C1 and C2

Abstract

The X-chromosome-linked inhibitor of apoptosis, XIAP, is the most powerful and ubiquitous intrinsic inhibitor of apoptosis. We have shown previously that the translation of XIAP is controlled by a potent internal ribosome entry site (IRES) element. IRES-mediated translation of XIAP is increased in response to cellular stress, suggesting the critical role for IRES translation during cellular stress. Here, we demonstrate that heterogeneous nuclear ribonucleoproteins C1 and C2 (hnRNPC1 and -C2) are part of the RNP complex that forms on XIAP IRES. Furthermore, the cellular levels of hnRNPC1 and -C2 parallel the activity of XIAP IRES and the overexpression of hnRNPC1 and -C2 specifically enhanced translation of XIAP IRES, suggesting that hnRNPC1 and -C2 may modulate XIAP expression. Given the central role of XIAP in the regulation of apoptosis these results are important for our understanding of the control of apoptosis.

ACKNOWLEDGMENTS

We thank the members of our laboratory for useful discussion. We are grateful to Gideon Dreyfuss for the generous gift of anti-hnRNPC monoclonal antibody 4F4 and to Adi Kimchi for the gift of FLAG epitope containing plasmid pECE.

This work was supported by grants from the Canadian Institutes of Health Research (CIHR), Medical Research Council of Canada (MRC), the Canadian Networks of Centers of Excellence (NCE), and the Howard Hughes Medical Institute (HHMI). R.G.K. is a recipient of an MRC Senior Scientist Award, a Fellow of the Royal Society of Canada, and an HHMI International Research Scholar. M.H. is a CIHR New Investigator.