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

Mol Endocrinol. 1999 Nov;13(11):1951-62. doi: 10.1210/mend.13.11.0377.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CYP51A1 protein, human
  • Cyp51 protein, rat
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Sterols
  • Transcription Factors
  • Cyclic AMP Response Element Modulator
  • Cytochrome P-450 Enzyme System
  • Cyclic AMP
  • Oxidoreductases
  • Cyp51 protein, mouse
  • Sterol 14-Demethylase
  • Farnesyl-Diphosphate Farnesyltransferase