Cholesterogenic lanosterol 14alpha-demethylase (CYP51) is an immediate early response gene.
Lanosterol 14alpha-demethylase (CYP51) responds to cholesterol feedback regulation through sterol regulatory element binding proteins (SREBPs). The proximal promoter of CYP51 contains a conserved region with clustered regulatory elements: GC box, cAMP-response elements (CRE-like), and sterol regulatory element (SRE). In lipid-rich (SREBP-poor) conditions, the CYP51 mRNA drops gradually, the promoter activity is diminished, and no DNA-protein complex is observed at the CYP51-SRE1 site. The majority of cAMP-dependent transactivation is mediated through a single CRE (CYP51-CRE2). Exposure of JEG-3 cells to forskolin, a mediator of the cAMP-dependent signaling pathway, provokes an immediate early response of CYP51, which has not been described before for any cholesterogenic gene. The CYP51 mRNA increases up to 4-fold in 2 h and drops to basal level after 4 h. The inducible cAMP early repressor (ICER) is involved in attenuation of transcription. Overexpressed CRE-binding protein (CREB)/CRE modulator (CREM) transactivates the mouse/human CYP51 promoters containing CYP51-CRE2 independently of SREBPs, and ICER decreases the CREB-induced transcription. Besides the increased CYP51 mRNA, forskolin affects the de novo sterol biosynthesis in JEG-3 cells. An increased consumption of lanosterol, a substrate of CYP51, is observed together with modulation of the postlanosterol cholesterogenesis, indicating that cAMP-dependent stimuli cross-talk with cholesterol feedback regulation. CRE-2 is essential for cAMP-dependent transactivation, whereas SRE seems to be less important. Interestingly, when CREB is not limiting, the increasing amounts of SREBP-1a fail to transactivate the CYP51 promoter above the CREB-only level, suggesting that hormones might have an important role in regulating cholesterogenesis in vivo.
Fink
Martina
M
Medical Center for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia.
Acimovic
Jure
J
Rezen
Tadeja
T
Tansek
Natasa
N
Rozman
Damjana
D
D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D017781:Genes, Immediate-Early; D006801:Humans; D008055:Lipids / Q000037:antagonists & inhibitors; D008322:Mammals / Q000235:genetics; D051379:Mice; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation
C548418:CYP51A1 protein, human; D008055:Lipids; D012333:RNA, Messenger; D013261:Sterols; D005576:Colforsin; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D000242:Cyclic AMP; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase