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cAMP opposes the glucose-mediated induction of the L-PK gene by preventing the recruitment of a complex containing ChREBP, HNF4, and CBP

Susan J. Burke^*, J. Jason Collier^, and Donald K. Scott^*,1

^* Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; and

Department of Pharmacology and Cancer Biology and

Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina, USA

¹ Correspondence: Division of Endocrinology, Department of Medicine, E1147 BST, 200 Lothrop St., Pittsburgh, PA 15261, USA. E-mail: dks23{at}pitt.edu

Glucose-mediated activation of the L-type pyruvate kinase (L-PK) gene is repressed by cAMP, making this an excellent model for studying the mechanism by which these contrary signals regulate gene expression. Using the 832/13 rat insulinoma cell line, we demonstrate using RNA interference and chromatin immunoprecipitation that carbohydrate response element binding protein (ChREBP), hepatic nuclear factor 4 (HNF4), and the coactivator CREB binding protein (CBP) are required for the glucose response of the L-PK gene and are recruited to the promoter by glucose. The cAMP agonist forskolin blocked the glucose-mediated induction of the L-PK gene in a PKA-dependent manner and blocked the recruitment of ChREBP, HNF4, and CBP to the L-PK promoter, while simultaneously recruiting CBP to the cAMP-inducible gene, nuclear receptor subfamily 4, group A, member 2 (NR4A2). Overexpression of CBP, but not ChREBP, reversed the cAMP repression of the L-PK gene. In addition, CBP augmented the glucose response of the L-PK promoter. We conclude that cAMP and glucose signaling converge on a complex containing ChREBP, HNF4, and CBP, and that cAMP acts by disrupting this transcriptional complex assembled by glucose-derived signals.—Burke, S. J., Collier, J. J., Scott, D. K. cAMP opposes the glucose-mediated induction of the L-PK gene by preventing the recruitment of a complex containing ChREBP, HNF4, and CBP.

Key Words: transcription • repression • promoter • signaling