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Papers In Press, published online ahead of print September 18, 2001
Department of Biology, Boston University, Boston, MA 02215
Corresponding Author: djw{at}bu.edu
STAT5b is repeatedly activated in rodent liver by the male pattern of intermittent plasma growth hormone (GH) stimulation and is required to maintain the GH pulse-regulated, male-specific pattern of liver gene expression. We presently investigate the interactions between STAT5b and hepatocyte-enriched nuclear factors (HNFs) that contribute to regulation of GH pulse-inducible, male-specific liver cytochrome P450 (CYP) genes. STAT5 binding sites were identified in the 5’-flank of the adult male-expressed genes CYP2A2 (nucleotides –2255 to -2247), CYP4A2 (-1872 to -1864) and CYP2C11 (-1150 to -1142). STAT5-DNA complexes were formed by each CYP sequence with nuclear extract from GH pulse-activated male, but not female, rat liver. The CYP2C11 STAT5 site, which is flanked by HNF3 consensus sequences, conferred STAT5b-inducible reporter gene activity in GH-treated HepG2 cells. trans-Activation of the intact CYP2C11 promoter (1.8 kb 5’-flank) was strongly induced by the liver nuclear factors HNF1a and HNF3b, but unexpectedly, was inhibited by GH-activated STAT5b. This STAT5b inhibitory effect could be reversed by HNF1a, and reflects a functional antagonism between STAT5b and HNF3b, as evidenced by the inhibition of HNF3b DNA-binding and transcriptional activity by STAT5b. HNF3b, in turn, inhibited STAT5b by a novel mechanism that leads to suppression of GH-inducible STAT5b tyrosine phosphorylation, DNA-binding and transcriptional activity. The potential for GH-activated STAT5b to stimulate male-specific liver CYP expression can thus be modulated by HNF3b, highlighting the complex interrelationship between STAT5b and liver transcription factors controlling expression of GH-regulated CYP genes.
J. Biol. Chem, 10.1074/jbc.M107597200
Submitted on August 9, 2001
Revised on September 6, 2001
Accepted on September 17, 2001
Inhibitory cross-talk between STAT5b and liver nuclear factor HNF3beta. Impact on the regulation of growth hormone pulse-stimulated, male-specific liver cytochrome P450 gene expression
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