Regulation of internal ribosome entry site-mediated translation by eukaryotic initiation factor-2α phosphorylation and translation of a small upstream open reading frame

James Fernandez, Ibrahim Yaman, William C. Merrick, Antonis Koromilas, Ronald Wek, Rushira Sood, Jack Hensold, Maria Hatzoglou

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Adaptation to amino acid deficiency is critical for cell survival. In yeast, this adaptation involves phosphorylation of the translation eukaryotic initiation factor (eIF) 2α by the kinase GCN2. This leads to the increased translation of the transcription factor GCN4, which in turn increases transcription of amino acid biosynthetic genes, at a time when expression of most genes decreases. Here it is shown that translation of the arginine/lysine transporter cat-1 mRNA increases during amino acid starvation of mammalian cells. This increase requires both GCN2 phosphorylation of eIF2α and the translation of a 48-amino acid upstream open reading frame (uORF) present within the 5′-leader of the transporter mRNA. When this 5′-leader was placed in a bicistronic mRNA expression vector, it functioned as an internal ribosomal entry sequence and its regulated activity was dependent on uORF translation. Amino acid starvation also induced translation of monocistronic mRNAs containing the cat-1 5′-leader, in a manner dependent on eIF2α phosphorylation and translation of the 48-amino acid uORF. This is the first example of mammalian regulation of internal ribosomal entry sequence-mediated translation by eIF2α phosphorylation during amino acid starvation, suggesting that the mechanism of induced Cat-1 protein synthesis is part of the adaptive response of cells to amino acid limitation.

Original languageEnglish
Pages (from-to)2050-2058
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number3
DOIs
StatePublished - Jan 18 2002

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Eukaryotic Initiation Factor-2
Phosphorylation
Open Reading Frames
Amino Acids
Starvation
Messenger RNA
Cats
Genes
Cells
Internal Ribosome Entry Sites
Protein Biosynthesis
Transcription
Yeast
Lysine
Arginine
Cell Survival
Transcription Factors
Phosphotransferases
Yeasts
Gene Expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of internal ribosome entry site-mediated translation by eukaryotic initiation factor-2α phosphorylation and translation of a small upstream open reading frame. / Fernandez, James; Yaman, Ibrahim; Merrick, William C.; Koromilas, Antonis; Wek, Ronald; Sood, Rushira; Hensold, Jack; Hatzoglou, Maria.

In: Journal of Biological Chemistry, Vol. 277, No. 3, 18.01.2002, p. 2050-2058.

Research output: Contribution to journalArticle

Fernandez, James ; Yaman, Ibrahim ; Merrick, William C. ; Koromilas, Antonis ; Wek, Ronald ; Sood, Rushira ; Hensold, Jack ; Hatzoglou, Maria. / Regulation of internal ribosome entry site-mediated translation by eukaryotic initiation factor-2α phosphorylation and translation of a small upstream open reading frame. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 3. pp. 2050-2058.
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