Nutritional control of mRNA stability is mediated by a conserved AU-rich element that binds the cytoplasmic shuttling protein HuR.
The cationic amino acid transporter, Cat-1, is a high affinity transporter of the essential amino acids, arginine and lysine. Expression of the cat-1 gene increases during nutritional stress as part of the adaptive response to starvation. Amino acid limitation induces coordinate increases in stability and translation of the cat-1 mRNA, at a time when global protein synthesis decreases. It is shown here that increased cat-1 mRNA stability requires an 11 nucleotide AU-rich element within the distal 217 bases of the 3'-untranslated region. When this 217-nucleotide nutrient sensor AU-rich element (NS-ARE) is present in a chimeric mRNA it confers mRNA stabilization during amino acid starvation. HuR is a member of the ELAV family of RNA-binding proteins that has been implicated in regulating the stability of ARE-containing mRNAs. We show here that the cytoplasmic concentration of HuR increases during amino acid starvation, at a time when total cellular HuR levels decrease. In addition, RNA gel shift experiments in vitro demonstrated that HuR binds to the NS-ARE and binding was dependent on the 11 residue AU-rich element. Moreover, HuR binding to the NS-ARE in extracts from amino acid-starved cells increased in parallel with the accumulation of cytoplasmic HuR. It is proposed that an adaptive response of cells to nutritional stress results in increased mRNA stability mediated by HuR binding to the NS-ARE.
Yaman
Ibrahim
I
Departments of Nutrition and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106-4906, USA.
Fernandez
James
J
Sarkar
Bedabrata
B
Schneider
Robert J
RJ
Snider
Martin D
MD
Nagy
Laura E
LE
Hatzoglou
Maria
M
D020413:3' Untranslated Regions / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface; D001483:Base Sequence; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D024202:Electrophoretic Mobility Shift Assay; D008969:Molecular Sequence Data; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured
D020413:3' Untranslated Regions; D000596:Amino Acids; D000954:Antigens, Surface; D027201:Cationic Amino Acid Transporter 1; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins