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

T Kawaguchi, M Takenoshita… - Proceedings of the …, 2001 - National Acad Sciences
T Kawaguchi, M Takenoshita, T Kabashima, K Uyeda
Proceedings of the National Academy of Sciences, 2001National Acad Sciences
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 …
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.
National Acad Sciences