Michael Waterman
Faculty Member
Last active: 2/12/2015

Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids.

Rozman D, Fink M, Fimia GM, Sassone-Corsi P, Waterman MR
Mol Endocrinol. 1999 13 (11): 1951-62

PMID: 10551787 · DOI:10.1210/mend.13.11.0377

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.

MeSH Terms (26)

Animals Base Sequence CCAAT-Enhancer-Binding Proteins Cyclic AMP Cyclic AMP Response Element Modulator Cytochrome P-450 Enzyme System DNA-Binding Proteins Farnesyl-Diphosphate Farnesyltransferase Gene Expression Profiling Humans Male Mice Molecular Sequence Data Nuclear Proteins Oxidoreductases Promoter Regions, Genetic Rats Rats, Sprague-Dawley Repressor Proteins Response Elements Spermatids Sterol 14-Demethylase Sterol Regulatory Element Binding Protein 1 Sterols Testis Transcription Factors

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