Abstract
The insulin-like growth factor I receptor (IGF-IR) is a heterotetrameric receptor mediating the effects of insulin-like growth I and other growth factors. This receptor is encoded by an mRNA containing an unusually long, G-C-rich, and highly structured 5' untranslated region. Using bicistronic constructs, we demonstrated here that the 5' untranslated region of the IGF-IR allows translation initiation by internal ribosome entry and therefore constitutes an internal ribosome entry site. In vitro cross-linking revealed that this internal ribosome entry site binds a protein of 57 kDa. Immunoprecipitation of UV cross-linked proteins proved that this protein was the polypyrimidine tract-binding protein, a well known regulator of picornavirus mRNA 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 elements that allow translation initiation to occur by internal initiation. Because the IGF-IR has a pivotal function in the cell cycle, this mechanism of translation regulation could play a crucial role in the control of cell proliferation and differentiation.
Highlights
Insulin-like growth factor I (IGF-I)1 is a ubiquitous peptide that has a fundamental role in both prenatal and postnatal development [1, 2]
Predictions of the rat and human IGF-I receptor (IGF-IR) 5Ј untranslated regions (UTRs) secondary structures were performed using Zucker’s algorithm, and the structures were folded with the ESSA software (Fig. 1) [34]
In cells transfected with pBiC-⌬, which contains only a part of the sequence coding for the 5Ј UTR of the IGF-IR, translation of the Firefly Luciferase reporter gene (FLuc) gene was reduced because the ratio was only 3-fold higher than that obtained with the pBiC vector
Summary
Insulin-like growth factor I (IGF-I)1 is a ubiquitous peptide that has a fundamental role in both prenatal and postnatal development [1, 2]. We provide evidence for the first time that the mRNA encoding a growth factor receptor (IGF-IR) is translated by an internal initiation mechanism.
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