Steroidogenic factor-1 mediates cyclic 3',5'-adenosine monophosphate regulation of the high density lipoprotein receptor.
The high density lipoprotein (HDL) receptor mediates the uptake of cholesterol and cholesteryl esters, substrates for steroidogenesis, from an HDL particle in the adrenal gland and gonads. We report here that treatment of rat luteal cells with 1 mM (Bu)2cAMP for 24 h dramatically induced (118-fold) HDL receptor messenger RNA levels. The rat HDL receptor promoter contains a steroidogenic factor-1 (SF-1)-binding site (SFBd; 5'-TCAAGGCC-3') through which SF-1 protein binds and activates transcription of this gene in both human HTB9 bladder carcinoma and mouse Y1 tumor cells, an effect that is enhanced by cAMP. These observations demonstrate that this motif is required for both basal and cAMP-induced regulation of the HDL receptor gene. Cotransfection studies in Kin 8 cells, a Y1 cell line resistant to cAMP activation as a result of a mutation in the protein kinase A (PKA) regulatory subunit, showed that a functional PKA is required for cAMP induction of HDL receptor gene transcription. Deleting the activation function-2 domain (amino acids 448-461) or mutating Ser430, a potential consensus phosphorylation site for PKA in the SF-1 protein, decreased both basal and cAMP-induced activation of the HDL receptor promoter. These data suggest that these regions within the SF-1 protein are required for both basal and cAMP-induced regulation of the HDL receptor gene. The mediation of cAMP responsiveness of the HDL receptor gene by SF-1 suggests how important this trans-acting factor is in steroid hormone synthesis by assuring that all required elements (substrate and enzymes) are present when they are needed for maximal steroid production.
Lopez
D
D
Department of Obstetrics and Gynecology, University of South Florida College of Medicine, Tampa 33606, USA.
Sandhoff
T W
TW
McLean
M P
MP
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002352:Carrier Proteins; D002478:Cells, Cultured; D003338:Corpus Luteum / Q000166:cytology / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins; D006801:Humans; D008075:Lipoproteins, HDL; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D008075:Lipoproteins, HDL; C515057:NR5A1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018110:Receptors, Lipoprotein; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C031616:high density lipoprotein receptors; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat; C075197:high density lipoprotein binding protein; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases