The Human IGF1R IRES likely operates through a Shine–Dalgarno-like interaction with the G961 loop (E-site) of the 18S rRNA and is kinetically modulated by a naturally polymorphic polyU loop
Article first published online: 26 MAR 2010
Copyright © 2010 Wiley-Liss, Inc.
Journal of Cellular Biochemistry
Volume 110, Issue 2, pages 531–544, 15 May 2010
How to Cite
Meng, Z., Jackson, N. L., Shcherbakov, O. D., Choi, H. and Blume, S. W. (2010), The Human IGF1R IRES likely operates through a Shine–Dalgarno-like interaction with the G961 loop (E-site) of the 18S rRNA and is kinetically modulated by a naturally polymorphic polyU loop. J. Cell. Biochem., 110: 531–544. doi: 10.1002/jcb.22569
- Issue published online: 21 APR 2010
- Article first published online: 26 MAR 2010
- Manuscript Accepted: 3 FEB 2010
- Manuscript Received: 2 JAN 2010
- National Institutes of Health, National Cancer Institute. Grant Number: R01 CA108886
- regulation of gene expression at the translational level;
- 5′-untranslated sequence;
- allelic variation
IGF1R is a proto-oncogene with potent mitogenic and antiapoptotic activities, and its expression must be tightly regulated to maintain normal cellular and tissue homeostasis. We previously demonstrated that translation of the human IGF1R mRNA is controlled by an internal ribosome entry site (IRES), and delimited the core functional IRES to a 90-nucleotide segment of the 5′-untranslated region positioned immediately upstream of the initiation codon. Here we have analyzed the sequence elements that contribute to the function of the core IRES. The Stem2/Loop2 sequence of the IRES exhibits near-perfect Watson–Crick complementarity to the G961 loop (helix 23b) of the 18S rRNA, which is positioned within the E-site on the platform of the 40S ribosomal subunit. Mutations that disrupt this complementarity have a negative impact on regulatory protein binding and dramatically decrease IRES activity, suggesting that the IGF1R IRES may recruit the 40S ribosome by a eukaryotic equivalent of the Shine–Dalgarno (mRNA–rRNA base-pairing) interaction. The homopolymeric Loop3 sequence of the IRES modulates accessibility and limits the rate of translation initiation mediated through the IRES. Two functionally distinct allelic forms of the Loop3 poly(U)-tract are prevalent in the human population, and it is conceivable that germ-line or somatic variations in this sequence could predispose individuals to development of malignancy, or provide a selectable growth advantage for tumor cells. J. Cell. Biochem. 110: 531–544, 2010. © 2010 Wiley-Liss, Inc.