Translation initiation of the insulin-like growth factor I receptor mRNA is mediated by an internal ribosome entry site

The insulin-like growth factor I receptor (IGF-IR) is a heterotetrameric re ceptor mediating the effects of insulin-like growth I and other growth fact ors. This receptor is encoded by an mRNA containing an unusually long, G-C- rich, and highly structured 5 ' untranslated region. Using bicistronic cons tructs, we demonstrated here that the 5 ' untranslated region of the IGF-IR allows translation initiation by internal ribosome entry and therefore con stitutes an internal ribosome entry site. In vitro cross-linking revealed t hat this internal ribosome entry site binds a protein of 57 kDa. Immunoprec ipitation of UV cross-linked proteins proved that this protein was the poly pyrimidine tract-binding protein, a well known regulator of picornavirus mR NA translation. The efficiency of translation of the endogenous IGF-IR mRNA is not affected by rapamycin, which is a potent inhibitor of cap-dependent translation. This result provides evidence that the endogenous IGF-IR mRNA is translated, at least in part, through a cap-independent mechanism. This is the first report of a growth factor receptor containing sequence elemen ts that allow translation initiation to occur by internal initiation. Becau se the IGF-IR has a pivotal function in the cell cycle, this mechanism of t ranslation regulation could play a crucial role in the control of cell prol iferation and differentiation.