STAT 5 and NF-Y are involved in expression and growth hormone-mediated sexually dimorphic regulation of cytochrome P450 3A10/lithocholic acid 6beta-hydroxylase.
The level of expression of a number of sexually differentiated liver proteins is primarily determined by plasma growth hormone (GH). Adult males have a pulsatile profile of GH release, while females have a relatively steady-state pattern of GH release. An important subset of these sexually differentiated hepatic proteins is certain cytochrome P450s (P450s). CYP3A10/6beta-hydroxylase is a male-specific P450 that catalyzes 6beta-hydroxylation of lithocholic acid, and the pattern of GH secretion is directly responsible for male-specific expression of this gene. The DNA element involved in GH-mediated regulation of CYP3A10/6beta-hydroxylase promoter activity binds a member of the STAT (signal transducers and activators of transcription) family of proteins. In this study we functionally demonstrate that two members of the STAT family, STAT 5a and STAT 5b, mediate GH-dependent regulation of CYP3A10/6beta-hydroxylase promoter activity. Furthermore, a neighboring DNA element binds NF-Y, a transcription factor involved in maintaining high levels of transcription of many genes and known to functionally interact with other factors. In the CYP3A10/6beta-hydroxylase gene, NF-Y also modulates binding of STAT 5, thereby modulating GH-mediated activation of its transcription.
Subramanian
A
A
Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, PO Box 980614, Richmond, VA 23298-0614, USA.
Wang
J
J
Gil
G
G
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D022762:CCAAT-Enhancer-Binding Proteins; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072469:Cytochrome P450 Family 3; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000378:metabolism*; D008647:Mesocricetus; D008894:Milk Proteins; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050799:STAT5 Transcription Factor; D012727:Sex Characteristics; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D000072469:Cytochrome P450 Family 3; C071543:cytochrome P450 CYP3A10 (hamster)