Role of hepatocyte nuclear factors in transcriptional regulation of male-specific CYP2A2

J Biol Chem. 2005 Feb 4;280(5):3259-68. doi: 10.1074/jbc.M409294200. Epub 2004 Nov 10.

Abstract

Cytochrome P450 2A2 (CYP2A2) is an adult male-specific rat liver steroid hydroxylase whose sex-dependent expression is regulated at the transcriptional level by sexually dimorphic pituitary growth hormone (GH) secretory patterns. In contrast to CYP2C11 and other male-specific, plasma GH pulse-inducible liver genes, CYP2A2 is highly expressed in hypophysectomized rat liver, despite the absence of GH stimulation. CYP2A2 promoter fragments 0.9-6.2 kb long exhibited unusually high basal promoter activity when transfected into the liver cell line HepG2. A further approximately 2.5-fold increase in activity was obtained by cotransfection of hepatocyte nuclear factor (HNF) 3gamma or HNF4alpha. CYP2A2 promoter activity was inhibited approximately 85% by transfection of HNF3beta or HNF6, both of which are more highly expressed in female than male liver and can strongly trans-activate the female-specific CYP2C12 promoter. The male GH pulse-activated transcription factor STAT5b had no effect on CYP2A2 promoter activity, either alone or in combination with HNF3gamma and HNF4alpha, consistent with the GH pulse-independence of CYP2A2 expression. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4alpha toward two other male-specific liver target genes, Cyp2d9 and CYP8B1. Furthermore, STAT5b in combination with the HNF4alpha coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha strongly enhanced the transcriptional activity of HNF4alpha toward CYP8B1 but not toward CYP2A2. These findings support the hypothesis that sex-dependent HNFs contribute to the sexually dimorphic expression of CYP2A2 and other liver CYPs and highlight the ability of STAT5b to act in concert with HNF4alpha to regulate select male-specific liver CYP genes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • COS Cells
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 2
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Hepatocyte Nuclear Factor 3-beta
  • Hepatocyte Nuclear Factor 3-gamma
  • Hepatocyte Nuclear Factor 4
  • Hepatocyte Nuclear Factor 6
  • Hepatocytes / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Liver Neoplasms
  • Male
  • Mice
  • Milk Proteins / genetics
  • Milk Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic / physiology
  • Rabbits
  • Rats
  • STAT5 Transcription Factor
  • Sex Characteristics*
  • Steroid 12-alpha-Hydroxylase / genetics
  • Steroid 16-alpha-Hydroxylase / genetics
  • Steroid Hydroxylases / genetics*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptional Activation / physiology*

Substances

  • DNA-Binding Proteins
  • Foxa2 protein, mouse
  • Foxa2 protein, rat
  • Foxa3 protein, mouse
  • Foxa3 protein, rat
  • Hepatocyte Nuclear Factor 4
  • Hepatocyte Nuclear Factor 6
  • Hnf4a protein, mouse
  • Hnf4a protein, rat
  • Homeodomain Proteins
  • Milk Proteins
  • Nuclear Proteins
  • Onecut1 protein, mouse
  • Onecut1 protein, rat
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphoproteins
  • Ppargc1a protein, mouse
  • STAT5 Transcription Factor
  • Stat5b protein, mouse
  • Stat5b protein, rat
  • Trans-Activators
  • Transcription Factors
  • Hepatocyte Nuclear Factor 3-gamma
  • Hepatocyte Nuclear Factor 3-beta
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C11 protein, rat
  • CYP2D9 protein, mouse
  • Cytochrome P450 Family 2
  • Steroid 16-alpha-Hydroxylase
  • steroid hormone 7-alpha-hydroxylase
  • Steroid 12-alpha-Hydroxylase