Internal ribosome entry site-mediated translation of a mammalian mRNA is regulated by amino acid availability

The cationic amino acid transporter, Cat-1, facilitates the uptake of the e ssential amino acids arginine and lysine, Amino acid starvation causes accu mulation and increased translation of cat-1 mRNA, resulting in a 58-fold in crease in protein levels and increased arginine uptake. A bicistronic mRNA expression system was used to demonstrate the presence of an internal ribos omal entry sequence (IRES) within the 5'-untranslated region of the cat-1 m RNA. This study shows that IRES-mediated translation of the cat-1 mRNA is r egulated by amino acid availability. This IRES causes an increase in transl ation under conditions of amino acid starvation. In contrast, cap-dependent protein synthesis is inhibited during amino acid starvation, which is well correlated with decreased phosphorylation of the cap-binding protein, eIF4 E. These findings reveal a new aspect of mammalian gene expression and regu lation that provides a cellular stress response; when the nutrient supply i s limited, the activation of IRES mediated translation of mammalian mRNAs r esults in the synthesis of proteins essential for cell survival.