Transcriptional regulation of P450scc gene expression in the embryonic rodent nervous system.
Steroid hormones are synthesized in adrenals, gonads, placenta, and the central and peripheral nervous systems (neurosteroids). Neurosteroidogenesis, like conventional steroidogenesis, begins with the conversion of cholesterol to pregnenolone, catalyzed by mitochondrial P450 side-chain cleavage enzyme (P450scc). Transcription of the P450scc gene in the adrenals and gonads requires steroidogenic factor-1, which is not expressed in the nervous system cells that express P450scc. A crucial transcriptional regulatory region of the rat P450scc gene is at -130/-94. We have purified two nuclear proteins (70 and 86 kDa) from rat glial C6 cells that specifically bind to the -130/-94 region of the rat P450scc promoter and identified them as the DNA-binding subunits of autoimmune antigen Ku. Ku colocalized with P450scc in several regions of the nervous system, but its overexpression in C6 cells did not augment transcription from a -130/-94 Luciferase construct. Members of the Sp family of transcription factors also bind to the same DNA sequence as Ku. Sp4 and Sp2 colocalize with P450scc in the nervous system early in development, whereas Sp1 and Sp4 colocalize later in development. Sp1 robustly increased transcription from this element in Sp-deficient Drosophila SL2 cells, and Ku synergistically enhanced this Sp1-stimulated transcription. Thus, members of the Sp transcription family play a role in activating P450scc gene transcription in the nervous system, and Ku may further augment this activation.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, 513 Parnassus Avenue, Box 0556, San Francisco, CA 94143-0556, USA.
Fabian
F
Hammer
Nathalie A
NA
Compagnone
Jean-Louis
JL
Vigne
Susanna R
SR
Bair
Synthia H
SH
Mellon
D000818:Animals; D034961:Antigens, Nuclear / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens; D001665:Binding Sites; D001921:Brain / Q000196:embryology; D001923:Brain Chemistry; D002460:Cell Line; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000032:analysis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004330:Drosophila; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D000072200:Ku Autoantigen; D051379:Mice; D009457:Neuroglia; D009687:Nuclear Proteins / Q000737:chemistry / Q000302:isolation & purification; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D051704:Sp2 Transcription Factor; D051706:Sp4 Transcription Factor; D054339:Steroidogenic Factor 1; D014018:Tissue Distribution; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D034961:Antigens, Nuclear; D001324:Autoantigens; D004268:DNA-Binding Proteins; C515057:NR5A1 protein, human; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; C497120:Sp2 protein, rat; D051706:Sp4 Transcription Factor; C497125:Sp4 protein, mouse; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat; D051704:Sp2 Transcription Factor; D004247:DNA; D002786:Cholesterol Side-Chain Cleavage Enzyme; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen