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 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.
Giraud
S
S
Division of Cardiology, University Hospital of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland and the INSERM Unité 369, Faculté de Médecine Lyon RTH Laennec, 7 Rue Guillaume Paradin, 69372 Lyon Cedex 08, France.
Greco
A
A
Brink
M
M
Diaz
J J
JJ
Delafontaine
P
P
D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009690:Nucleic Acid Conformation; D010442:Peptide Chain Initiation, Translational; D038941:Polypyrimidine Tract-Binding Protein; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D012261:Ribonucleoproteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
D020121:5' Untranslated Regions; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D038941:Polypyrimidine Tract-Binding Protein; D017526:Receptor, IGF Type 1; D020123:Sirolimus