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CCAAT/Enhancer-Binding Protein- Is a Component of the Growth Hormone-Regulated Network of Liver Transcription Factors¹

Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, Brussels 1200, Belgium

Address all correspondence and requests for reprints to: Dr. Frédéric P. Lemaigre, avenue Hippocrate 75, Box 7529, 1200 Brussels, Belgium. E-mail: lemaigre{at}horm.ucl.ac.be

GH regulates gene expression by modulating the concentration or activity of transcription factors. To identify transcription factors that mediate the effects of GH in liver we analyzed the promoter of the gene coding for hepatocyte nuclear factor-6 (HNF-6), whose expression in liver is stimulated by GH. In protein-DNA interaction studies and in transfection experiments, we found that the liver-enriched transcription factor CCAAT/enhancer-binding protein- (C/EBP) binds to the hnf6 gene and inhibits its expression. This inhibitory effect involved an N-terminal subdomain of C/EBP and two sites in the hnf6 gene promoter. Using liver nuclear extracts from GH-treated hypophysectomized rats, we found that GH induces a rapid, transient decrease in the amount of C/EBP protein. This GH-induced change is concomitant with the transient stimulatory effect of GH on the hnf6 gene. Stimulation of the hnf6 gene by GH therefore involves lifting of the repression exerted by C/EBP in addition to the known GH-induced stimulatory effects of STAT5 (signal transducer and activator of transcription-5) and HNF-4 on that gene. Our data provide further evidence that GH controls a network of liver transcription factors and show that C/EBP participates in this process.

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