Characterization of the promoter region of the mouse gene encoding the steroidogenic acute regulatory protein.
Steroidogenic acute regulatory protein (StAR) delivers cholesterol to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroid hormone biosynthesis. StAR expression is restricted to steroidogenic cells and is rapidly induced by treatment with trophic hormones or cAMP. We analyzed the 5'-flanking region of the mouse StAR gene to elucidate the mechanisms that regulate its cell-specific and hormone-induced expression. In transient transfection assays, a luciferase reporter gene driven by the StAR 5'-flanking region was preferentially expressed by steroidogenic Y1 adrenocortical and MA-10 Leydig cells in a cAMP-responsive manner. 5'-Deletion and site-directed mutagenesis studies identified a region between -254 and -113 that is essential for full levels of promoter activity. This region contains a binding site for the orphan nuclear receptor steroidogenic factor-1 (SF-1) that, although not required for hormone induction, is critical for basal promoter activity, thus implicating SF-1 in StAR expression. Analyses of knockout mice deficient in SF-1 further supported an important role for SF-1 in StAR gene expression. These studies provide novel insights into the mechanisms that regulate StAR gene expression and extend our understanding of SF-1's global roles within steroidogenic cells.
Caron
K M
KM
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Ikeda
Y
Y
Soo
S C
SC
Stocco
D M
DM
Parker
K L
KL
Clark
B J
BJ
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D051717:Fushi Tarazu Transcription Factors; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins; D006728:Hormones / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D006728:Hormones; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; C515058:steroidogenic factor 1, mouse; D003609:Dactinomycin; D000242:Cyclic AMP