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J. Biol. Chem., Vol. 276, Issue 46, 43031-43039, November 16, 2001
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From the Division of Cell and Molecular Biology, Department of
Biology, Boston University, Boston, Massachusetts 02215
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 P-450 (CYP) genes. STAT5 binding sites
were identified in the 5'-flank of the adult male-expressed genes
CYP2A2 (nucleotides 
2255 to 2247), CYP4A2
(nucleotides 1872 to 1864), and CYP2C11 (nucleotides
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-kilobase 5'-flank) was strongly induced by the liver nuclear factors HNF1
and HNF3
but,
unexpectedly, was inhibited by GH-activated STAT5b. This STAT5b
inhibitory effect could be reversed by HNF1 and reflects a
functional antagonism between STAT5b and HNF3, as evidenced by the
inhibition of HNF3 DNA binding and transcriptional activity by
STAT5b. HNF3, in turn, inhibited STAT5b by a novel mechanism that
leads to suppression of GH-inducible STAT5b tyrosine phosphorylation,
DNA binding activity, and transcriptional activity. The potential for
GH-activated STAT5b to stimulate male-specific liver CYP
expression can thus be modulated by HNF3, highlighting the complex
interrelationship between STAT5b and liver transcription factors
controlling expression of GH-regulated CYP genes.
To whom correspondence should be addressed: Dept. of Biology,
Boston University, Boston, MA 02215. Fax: 617-353-7404; E-mail: djw@bu.edu.
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