Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids.
Lanosterol 14alpha-demethylase (CYP51) produces MAS sterols, intermediates in cholesterol biosynthesis that can reinitiate meiosis in mouse oocytes. As a cholesterogenic gene, CYP51 is regulated by a sterol/sterol-regulatory element binding protein (SREBP)-dependent pathway in liver and other somatic tissue. In testis, however, cAMP/cAMP-responsive element modulator CREMtau-dependent regulation of CYP51 predominates, leading to increased levels of shortened CYP51 mRNA transcripts. CREM-/- mice lack the abundant germ cell-specific CYP51 mRNAs in testis while expression of somatic CYP51 transcripts is unaffected. The mRNA levels of squalene synthase (an enzyme preceding CYP51 in cholesterol biosynthesis in testis of CREM-/- mice are unchanged as compared with wild-type animals, showing that regulation by CREMtau is not characteristic for all cholesterogenic genes expressed during spermatogenesis. The -334/+314 bp CYP51 region can mediate both the sterol/SREBP-dependent as well as the cAMP/CREMtau-dependent transcriptional activation. SREBP-1a from somatic cell nuclear extracts binds to a conserved CYP51-SRE1 element in the CYP51 proximal promoter. The cAMP-dependent transcriptional activator CREMtau from germ cell nuclear extracts binds to a conserved CYP51-CRE2 element while no SREBP-1 binding is observed in germ cells. The two regulatory pathways mediating expression of CYP51 describe this gene as a cholesterogenic gene (SREBP-dependent expression in liver and other somatic cells) and also as a haploid expressed gene (CREMtau-dependent expression in haploid male germ cells). While in somatic cells all genes involved in cholesterol biosynthesis are regulated coordinately by the sterol/SREBP-signaling pathway, male germ cells contain alternate routes to control expression of cholesterogenic genes.
Rozman
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Institute of Biochemistry, Medical Center for Molecular Biology, Medical Faculty University of Ljubljana, Slovenia. rozman@ibmi.mf.uni-lj.si
Fink
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M
Fimia
G M
GM
Sassone-Corsi
P
P
Waterman
M R
MR
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D000242:Cyclic AMP / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins; D020218:Response Elements / Q000502:physiology*; D013087:Spermatids / Q000378:metabolism*; D058886:Sterol 14-Demethylase; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000378:metabolism; D013737:Testis / Q000502:physiology; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; C548418:CYP51A1 protein, human; C548417:Cyp51 protein, rat; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D010088:Oxidoreductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D013186:Farnesyl-Diphosphate Farnesyltransferase