Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress

Charlie C. Huang, Yi Li, Alex B. Lopez, Cheng Ming Chiang, Randal J. Kaufman, Martin D. Snider, Maria Hatzoglou

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Expression of the Cat-1 gene (cationic amino acid transporter-1) is induced in proliferating cells and in response to a variety of stress conditions. The expression of the gene is mediated via a TATA-less promoter. In the present study we show that an Sp1 (specificity protein 1)-binding site within a GC-rich region of the Cat-1 gene controls its basal expression and is important for induction of the gene during the UPR (unfolded protein response). We have shown previously that induction of Cat-1 gene expression during the UPR requires phosphorylation of the translation initiation factor eIF2α (eukaryotic initiation factor 2α) by PERK (protein-kinase-receptor-like endoplasmic reticulum kinase), one of the signalling pathways activated during the UPR. This leads to increased translation of the transcription factor ATF4 (activating transcription factor 4).We also showthat a second signalling pathway is required for sustained transcriptional induction of the Cat-1 gene during the UPR, namely activation of IRE1 (inositol-requiring enzyme 1) leading to alternative splicing of the mRNA for the transcription factor XBP1 (X-box-binding protein 1). The resulting XBP1s (spliced XBP1) can bind to an ERSE (endoplasmic- reticulum-stress-response-element), ERSEII-like, thatwas identified within the Cat-1 promoter. Surprisingly, eIF2α phosphorylation is required for accumulation of XBP1s. We propose that the signalling via phosphorylated eIF2α is required for maximum induction of Cat-1 transcription during the UPR by inducing the accumulation of both ATF4 and XBP1s.

Original languageEnglish (US)
Pages (from-to)215-224
Number of pages10
JournalBiochemical Journal
Volume429
Issue number1
DOIs
StatePublished - Jul 1 2010

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Keywords

  • Activating transcription factor 4 (ATF4)
  • Cationic amino acid transporter-1 (Cat-1)
  • Endoplasmic reticulum stress
  • Specificity protein 1 (Sp1)
  • Unfolded protein response
  • X-box-binding protein 1 (XBP1)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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