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Submitted on March 12, 2004
Accepted on September 16, 2004
AND C/EBP MARKEDLY POTENTIATES THE PROTEIN KINASE A STIMULATION OF THE GLUCOSE-6-PHOSPHATASE PROMOTER
INSERM U.449/INRA 1235/UCB Lyon 1, Institut Fédératif de Recherche Laennec, rue Guillaume Paradin, 69372 Lyon cedex 08, France
* To whom correspondence should be addressed. E-mail: Amandine.Gautier{at}univ-lyon1.fr.
Glucose-6-phosphatase 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 for instance 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 PKA responsiveness of the glucose-6-phosphatase promoter. Using different molecular approaches, we demonstrate that HNF4
, C/EBP, C/EBP
and 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/EBP are constitutively bound to the endogenous Glc6Pase gene, while CREB and CBP will be to the gene upon stimulation by cAMP. These data strongly suggest that the cAMP responsiveness of the glucose-6-phosphatase 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.
•
C/EBP •
HNF4 •
CREB •
cAMP •
gluconeogenesis
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