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A Distal Region Involving Hepatocyte Nuclear Factor 4 and CAAT/Enhancer Binding Protein Markedly Potentiates the Protein Kinase A Stimulation of the Glucose-6-Phosphatase Promoter

Institut National de la Santé et de la Recherche Médicale, Unité 449/Institut National de la Recherche Agronomique 1235/Université Claude Bernard Lyon 1, Institut Fédératif de Recherche Laennec, 69372 Lyon cedex 08, France

Address all correspondence and requests for reprints to: Dr. Amandine Gautier-Stein, Institut National de la Santé et de la Recherche Médicale, Unité 449-Faculté de Médecine Laennec, Rue Guillaume Paradin-69372 Lyon cedex 08, France. E-mail: Amandine.Gautier{at}univ-lyon1.fr.

Glucose-6-phosphatase (Glc6Pase) is the last enzyme of gluconeogenesis and is only expressed in the liver, kidney, and small intestine. In these tissues, the mRNA and its activity are increased when cAMP levels increased (e.g. in fasting or diabetes). We first report that a proximal region (within –200 bp relative to the transcription start site) and a distal region (–694/–500 bp) are both required for a potent cAMP and a protein kinase A (PKA) responsiveness of the Glc6Pase promoter. Using different molecular approaches, we demonstrate that hepatocyte nuclear factor (HNF4), CAAT/ enhancer-binding protein- (C/EBP), C/EBPß, and cAMP response element-binding protein (CREB) are involved in the potentiated PKA responsiveness: in the distal region, via one HNF4- and one C/EBP-binding sites, and in the proximal region, via two HNF4 and two CREB-binding sites. We also show that HNF4, C/EBP, and C/EBPß are constitutively bound to the endogenous Glc6Pase gene, whereas CREB and CREB-binding protein (CBP) will be bound to the gene upon stimulation by cAMP. These data strongly suggest that the cAMP responsiveness of the Glc6Pase promoter requires a tight cooperation between a proximal and a distal region, which depends on the presence of several HNF4-, C/EBP-, and CREB-binding sites, therefore involving an intricate association of hepatic and ubiquitous transcription factors.

NURSA Molecule Pages Link:

Nuclear Receptors:   HNF4α

Coregulators:   PGC-1

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