Document Detail


Role of hepatocyte nuclear factors in transcriptional regulation of male-specific CYP2A2.
MedLine Citation:
PMID:  15539409     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Christopher A Wiwi; David J Waxman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-11-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-02-07     Completed Date:  2005-03-22     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3259-68     Citation Subset:  IM    
Affiliation:
Division of Cell and Molecular Biology, Department of Biology Boston University, Boston, Massachusetts 02215, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aryl Hydrocarbon Hydroxylases / genetics*
COS Cells
Carcinoma, Hepatocellular
Cell Line, Tumor
Cercopithecus aethiops
Cytochrome P-450 Enzyme System
DNA-Binding Proteins / genetics,  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,  metabolism
Liver Neoplasms
Male
Mice
Milk Proteins / genetics,  metabolism
Nuclear Proteins / genetics,  metabolism
Phosphoproteins / genetics,  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,  metabolism
Transcription Factors / genetics,  metabolism
Transcriptional Activation / physiology*
Grant Support
ID/Acronym/Agency:
DK33765/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Foxa2 protein, mouse; 0/Foxa2 protein, rat; 0/Foxa3 protein, mouse; 0/Foxa3 protein, rat; 0/Hepatocyte Nuclear Factor 4; 0/Hepatocyte Nuclear Factor 6; 0/Hnf4a protein, mouse; 0/Hnf4a protein, rat; 0/Homeodomain Proteins; 0/Milk Proteins; 0/Nuclear Proteins; 0/Onecut1 protein, mouse; 0/Onecut1 protein, rat; 0/Phosphoproteins; 0/Ppargc1a protein, mouse; 0/STAT5 Transcription Factor; 0/Stat5b protein, mouse; 0/Stat5b protein, rat; 0/Trans-Activators; 0/Transcription Factors; 135845-91-9/Hepatocyte Nuclear Factor 3-gamma; 135845-92-0/Hepatocyte Nuclear Factor 3-beta; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/Steroid 12-alpha-Hydroxylase; EC 1.14.-/Steroid Hydroxylases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C11 protein, rat; EC 1.14.14.1/CYP2D9 protein, mouse; EC 1.14.14.1/Steroid 16-alpha-Hydroxylase; EC 1.14.14.1/steroid hormone 7-alpha-hydroxylase

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