In the liver, induction of genes encoding enzymes involved in de novo lipogenesis occurs in response to increased glucose metabolism. ChREBP (carbohydrate-response-element-binding protein) is a basic helix–loop–helix/leucine zipper transcription factor that regulates expression of these genes. To evaluate the potential role of ChREBP phosphorylation in its regulation, we used MS to identify modified residues. In the present paper, we report the detection of multiple phosphorylation sites of ChREBP expressed in hepatocytes, several of which are only observed under high-glucose conditions. Mutation of each of these serine/threonine residues of ChREBP did not alter its ability to respond to glucose. However, mutation of five N-terminal phosphoacceptor sites resulted in a major decrease in activity under high-glucose conditions. These phosphorylated residues are located within a region of ChREBP (amino acids 1–197) that is critical for glucose regulation. Mutation of Ser56 within this region to an aspartate residue resulted in increased nuclear accumulation and activity under high-glucose conditions. Together, these data suggest that ChREBP activity is regulated by complex multisite phosphorylation patterns involving its N-terminal regulatory region.
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Research Article|
March 27 2008
Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP
Nikolas G. Tsatsos;
Nikolas G. Tsatsos
1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Michael N. Davies;
Michael N. Davies
1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Brennon L. O'callaghan;
Brennon L. O'callaghan
1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, U.S.A.
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Howard C. Towle
Howard C. Towle
1
1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, U.S.A.
1To whom correspondence should be addressed (email towle001@umn.edu).
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Publisher: Portland Press Ltd
Received:
August 22 2007
Revision Received:
December 12 2007
Accepted:
January 09 2008
Accepted Manuscript online:
January 09 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (2): 261–270.
Article history
Received:
August 22 2007
Revision Received:
December 12 2007
Accepted:
January 09 2008
Accepted Manuscript online:
January 09 2008
Citation
Nikolas G. Tsatsos, Michael N. Davies, Brennon L. O'callaghan, Howard C. Towle; Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP. Biochem J 15 April 2008; 411 (2): 261–270. doi: https://doi.org/10.1042/BJ20071156
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