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cAMP opposes the glucose‐mediated induction of the L‐PK gene by preventing the recruitment of a complex containing ChREBP, HNF4α, and CBP
Author(s) -
Burke Susan J.,
Collier J. Jason,
Scott Donald K.
Publication year - 2009
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/fj.08-126631
Subject(s) - carbohydrate responsive element binding protein , creb , chromatin immunoprecipitation , coactivator , creb binding protein , promoter , chemistry , transcription factor , gene , gene expression , biology , biochemistry
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 4a (HNF4α), 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, HNF4α, 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, HNF4α, 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, HNF4α, and CBP. FASEB J. 23, 2855‐2865 (2009). www.fasebj.org