Transcriptional regulation of the human sterol 27-hydroxylase gene (CYP27) and promoter mapping.
Recent evidence suggests that sterol 27-hydroxylase may play a role in cholesterol homeostasis and affect atherogenesis. The major objective of the study was to map and characterize the sterol 27-hydroxylase (CYP27) promoter region. Here we show that CYP27 gene has a TATA-less promoter and transcription initiates at a cluster of sites. The basic promoter is located between -166 and -187 bp from the translation initiation site. Possible positive transcription regulation sites are located at position -187 to -320 and -857 to -1087 bp. A negative transcription regulator site is located in position -320 to -413 bp. An enhancer sequence is located upstream to position -1087. CYP27 is upregulated by dexamethasone and downregulated by cyclosporin A and cholic acid. The dexamethasone responsive element is located between 1087 and 678 bp upstream to the putative ATG. Cyclosporin A affects bile acid metabolism by repressing CYP27 at the transcriptional level. The cyclosporin A- responsive element is mapped to between 1087 and 4000 bp upstream of the ATG. Cholic acid represses sterol 27-hydroxylase mRNA level by affecting the stability of its mRNA. The results obtained here imply that CYP27 has a potentially important role in cholesterol homeostasis in human cells, and is regulated by several substances that were previously shown to affect bile acid metabolism.
Segev
H
H
Department of Medicine, The Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah University Hospital, 91120, Jerusalem, Israel.
Honigman
A
A
Rosen
H
H
Leitersdorf
E
E
D001483:Base Sequence; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000378:metabolism; D019826:Cholic Acid / Q000494:pharmacology*; D002874:Chromosome Mapping; D016572:Cyclosporine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D005809:Genes, Regulator; D022781:Hepatocytes; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis*; D012680:Sensitivity and Specificity; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
D012333:RNA, Messenger; D003907:Dexamethasone; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D019826:Cholic Acid