Avtor/Urednik		Fink, Martina; Ačimovič, Jure; Režen, Tadeja; Tanšek, Nataša; Rozman, Damjana
Naslov		Cholesterogenic lanosterol 14alpha-demethylase (CYP51) is an immediate early response gene
Tip		članek
Vir		Endocrinology
Vol. in št.		Letnik 146, št. 12
Leto izdaje		2005
Obseg		str. 5321-31
Jezik		eng
Abstrakt		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 cAMPdependent 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 cAMPdependent transactivation, whereas SRE seems to be less important. Interestingly, when CREB is not limiting, the increasing amounts of SREBP-la fail to transactivate the CYP51 promoter above the CREB-only level, suggesting that hormones might have an important role in regulating cholesterogenesis in vivo.
Deskriptorji		OXIDOREDUCTASES GENES, IMMEDIATE-EARLY CYTOCHROME P-450 CHOLESTEROL CYCLIC AMP TRANS-ACTIVATION (GENETICS) TIME FACTORS SIGNAL TRANSDUCTION STEROLS RNA, MESSENGER PROMOTER REGIONS (GENETICS) LIPIDS TUMOR CELLS, CULTURED FORSKOLIN