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 essential amino acids arginine and lysine. Amino acid starvation causes accumulation and increased translation of cat-1 mRNA, resulting in a 58-fold increase in protein levels and increased arginine uptake. A bicistronic mRNA expression system was used to demonstrate the presence of an internal ribosomal entry sequence (IRES) within the 5'-untranslated region of the cat-1 mRNA. This study shows that IRES-mediated translation of the cat-1 mRNA is regulated by amino acid availability. This IRES causes an increase in translation 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, eIF4E. These findings reveal a new aspect of mammalian gene expression and regulation that provides a cellular stress response; when the nutrient supply is limited, the activation of IRES-mediated translation of mammalian mRNAs results in the synthesis of proteins essential for cell survival.
Fernandez
J
J
Departments of Nutrition and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106, USA.
Yaman
I
I
Mishra
R
R
Merrick
W C
WC
Snider
M D
MD
Lamers
W H
WH
Hatzoglou
M
M
D020121:5' Untranslated Regions; D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids / Q000378:metabolism*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism*
D020121:5' Untranslated Regions; D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger