Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein

T. Kawaguchi, M. Takenoshita, T. Kabashima, K. Uyeda

Research output: Contribution to journalArticle

252 Citations (Scopus)

Abstract

Recently we purified and identified a previously uncharacterized transcription factor from rat liver binding to the carbohydrate responsive element of the L-type pyruvate kinase (L-PK) gene. This factor was named carbohydrate responsive element binding protein (ChREBP). ChREBP, essential for L-PK gene transcription, is activated by high glucose and inhibited by cAMP. Here, we demonstrated that (i) nuclear localization signal and basic helix-loop-helix/leucine-zipper domains of ChREBP were essential for the transcription, and (ii) these domains were the targets of regulation by cAMP and glucose. Among three cAMP-dependent protein kinase phosphorylation sites, Ser196 and Thr666 were the target sites. Phosphorylation of the former resulted in inactivation of nuclear import, and that of the latter resulted in loss of the DNA-binding activity and L-PK transcription. On the other hand, glucose activated the nuclear import by dephosphorylation of Ser196 in the cytoplasm and also stimulated the DNA-binding activity by dephosphorylation of Thr666 in the nucleus. These results thus reveal mechanisms for regulation of ChREBP and the L-PK transcription by excess carbohydrate and cAMP.

Original languageEnglish (US)
Pages (from-to)13710-13715
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number24
DOIs
StatePublished - Nov 20 2001

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Pyruvate Kinase
Response Elements
Carrier Proteins
Phosphorylation
Carbohydrates
Glucose
Genes
Cell Nucleus Active Transport
Leucine Zippers
Nuclear Localization Signals
DNA
Cyclic AMP-Dependent Protein Kinases
Cytoplasm
Transcription Factors
Liver

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. / Kawaguchi, T.; Takenoshita, M.; Kabashima, T.; Uyeda, K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 24, 20.11.2001, p. 13710-13715.

Research output: Contribution to journalArticle

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