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Cholesterogenic Lanosterol 14-Demethylase (CYP51) Is an Immediate Early Response Gene

Martina Fink, Jure Aimovi, Tadeja Reen, Nataa Tanek and Damjana Rozman

Medical Center for Molecular Biology (M.F., N.T.), Center for Functional Genomics and Bio-Chips (J.A., T.R., D.R.), Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia

Address all correspondence and requests for reprints to: Prof. Damjana Rozman, Ph.D., Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Medical Faculty University of Ljubljana, Zaloka 4, 1000 Ljubljana, Slovenia. E-mail: damjana.rozman{at}mf.uni-lj.si.

Lanosterol 14-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.