Abstract
Growth hormone (GH) exerts sexually dimorphic effects on liver gene transcription through its sex-dependent temporal pattern of pituitary hormone secretion. CYP2C12 encodes a female-specific rat liver P450 steroid hydroxylase whose expression is activated by continuous GH stimulation of hepatocytes. Presently, we investigated the role of liver-enriched and GH-regulated transcription factors in the activation of CYP2C12 gene expression in GH-stimulated liver cells. Transcription of a CYP2C12 promoter-luciferase reporter gene in transfected HepG2 cells was activated 15-40-fold by the liver-enriched hepatocyte nuclear factor (HNF) 3 alpha, HNF3 beta, and HNF6. Synergistic interactions leading to an approximately 300-fold activation of the promoter by HNF3 beta in combination with HNF6 were observed. 5'-Deletion analysis localized the HNF6 response to a single 5'-proximal 96-nucleotide segment. By contrast, the stimulatory effects of HNF3 alpha and HNF3 beta were attributable to five distinct regions within the 1.6-kilobase CYP2C12 proximal promoter. GH activation of the signal transducer and transcriptional activator STAT5b, which proceeds efficiently in male but not female rat liver, inhibited CYP2C12 promoter activation by HNF3 beta and HNF6, despite the absence of a classical STAT5-binding site. The female-specific pattern of CYP2C12 expression is thus proposed to reflect the positive synergistic action in female liver of liver-enriched and GH-regulated transcription factors, such as HNF3 beta and HNF6, coupled with a dominant inhibitory effect of GH-activated STAT5b that is manifest in males.
Highlights
Growth hormone (GH) exerts sexually dimorphic effects on liver gene transcription through its sex-dependent temporal pattern of pituitary hormone secretion
Transcriptional Activation of 2C12 Promoter by Liver Transcription Factors HNF3 and HNF6 —GH-dependent expression of CYP2C12 mRNA requires ongoing protein synthesis [32], suggesting that CYP2C12 transcription may be regulated by a transcription factor that is itself regulated by GH at the level of gene expression
Because genes coding for several liver-enriched transcription factors are reported to be inducible by GH (e.g. Refs. 33 and 34), we examined the role of liver-enriched nuclear factors in CYP2C12 transactivation as determined by transient transfection into the human hepatoblastoma cell line HepG2
Summary
Growth hormone (GH) exerts sexually dimorphic effects on liver gene transcription through its sex-dependent temporal pattern of pituitary hormone secretion. GH activation of the signal transducer and transcriptional activator STAT5b, which proceeds efficiently in male but not female rat liver, inhibited CYP2C12 promoter activation by HNF3 and HNF6, despite the absence of a classical STAT5-binding site. The female-specific pattern of CYP2C12 expression is proposed to reflect the positive synergistic action in female liver of liver-enriched and GH-regulated transcription factors, such as HNF3 and HNF6, coupled with a dominant inhibitory effect of GH-activated STAT5b that is manifest in males. We have further established that a liver-expressed, latent cytoplasmic transcription factor, designated STAT5b, undergoes repeated tyrosine phosphorylation and nuclear translocation in direct response to the male pattern of GH secretion, leading us to propose that STAT5b is a transcriptional activator of malespecific, GH pulse-activated genes such as CYP2C11 [12, 13]. Further support for this proposal is provided by the correlation between STAT5b nuclear translocation and gender-specific P450 expression in mouse liver [17] and by the presence of bona fide STAT5-binding sites in the 5Ј-flanking region of
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