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Regulation of the Cat‐1 Gene by Physiological Stress
Author(s) -
Li Yi,
Lopez Alex,
Hatzoglou Maria
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a79-a
Subject(s) - atf4 , xbp1 , unfolded protein response , atf6 , transcription factor , biology , integrated stress response , microbiology and biotechnology , activating transcription factor 2 , activating transcription factor , response element , gene , gene expression , rna splicing , promoter , biochemistry , translation (biology) , messenger rna , endoplasmic reticulum , rna
Limitation of essential amino acids or accumulation of unfolded proteins in the ER induces a stress response that involves phosphorylation of the translation initiation factor eIF2 alpha. This adaptive response causes a transient decrease in global protein synthesis and increased expression of genes which are important for cell survival. Induction of the transcription factor ATF4 is an essential step in this adaptive response. In addition to the ATF4‐mediated response, the unfolded protein response (UPR) signaling involves two different transcription factors: XBP1s and ATF6. Expression of the Cat‐1 gene is induced by both the UPR and the amino acid starvation signaling pathway. We show here that induction of cat‐1 gene during amino acid starvation in C6 cells involves the transcription factor ATF4 that forms heterodimers with C/EBP beta and activate transcription via the amino acid response element TGATGAAAC. Our data also demonstrate that the regulation of the cat‐1 gene by the UPR response is closely related with the response to amino acid depletion. In C6 cells treated with thapsgargin that mobilizes sequestered Ca++ from the ER, cat‐1 gene transcription is stimulated via two different signaling pathways: the transcription factors XBP1 and ATF4. During ER stress, XBP1s is increased through splicing of the XPB1 mRNA by the stress‐activated protein IRE1?. ATF4 is up‐regulated through the PERK/eIF2? pathway. We have identified a DNA sequence within the cat‐1 gene promoter that is involved in regulation by XBP1s. Using luciferase‐reporter assays and chromatin immunoprecipitation assays using deficient MEFs of these transcription factors, we demonstrate that ATF4 and XBP1 are involved in inducing expression of the cat‐1 gene during amino acid starvation (ATF4) and the UPR (ATF4 and XBP1). The importance of cat‐1 gene regulation by the UPR in disease states such as diabetes will be discussed.