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Titolo:
TRANSCRIPTIONAL REGULATION OF THE RAT STEROIDOGENIC ACUTE REGULATORY PROTEIN GENE BY STEROIDOGENIC FACTOR-1
Autore:
SANDHOFF TW; HALES DB; HALES KH; MCLEAN MP;
Indirizzi:
UNIV S FLORIDA,DEPT OBSTET,COLL MED,4 COLUMBIA DR,ROOM 529 TAMPA FL 33606 UNIV S FLORIDA,DEPT OBSTET,COLL MED TAMPA FL 33606 UNIV S FLORIDA,DEPT GYNECOL,COLL MED TAMPA FL 33606 UNIV S FLORIDA,DEPT BIOCHEM & MOL BIOL,COLL MED TAMPA FL 33606 UNIV ILLINOIS,DEPT PHYSIOL & BIOPHYS CHICAGO IL 60612
Titolo Testata:
Endocrinology
fascicolo: 12, volume: 139, anno: 1998,
pagine: 4820 - 4831
SICI:
0013-7227(1998)139:12<4820:TROTRS>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
LEYDIG TUMOR-CELLS; ISOLATED ADRENAL-CELLS; SIDE-CHAIN CLEAVAGE; MITOCHONDRIAL PROTEINS; NUCLEAR RECEPTOR; HORMONE STIMULATION; CORTEX CELLS; LUTEAL CELLS; STAR GENE; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
T.W. Sandhoff et al., "TRANSCRIPTIONAL REGULATION OF THE RAT STEROIDOGENIC ACUTE REGULATORY PROTEIN GENE BY STEROIDOGENIC FACTOR-1", Endocrinology, 139(12), 1998, pp. 4820-4831

Abstract

Steroidogenic acute regulatory (StAR) protein is synthesized in response to tropic hormones to facilitate cholesterol transport to the inner mitochondrial membrane-bound P450 side-chain cleavage enzyme (P450scc), the first enzymatic step in the steroid hormone biosynthetic pathway. Gonadotropins activate expression of their target genes via the cAMP second messenger system. We have demonstrated that cAMP administration to rat luteal cells stimulates expression of both StAR messenger RNA and protein. Because cholesterol delivery is the first regulated step in steroidogenesis, and because StAR messenger RNA levels are increased in response to tropic hormone and cAMP stimulation, the mechanismby which tropic hormones/cAMP stimulate transcription needs to be elucidated. To this end, approximately 2.7 kb of the rat StAR promoter was isolated and sequenced. Sequence analysis revealed the presence of aTATA-like element as well as multiple regulatory motifs including steroidogenic factor 1 (SF-1) binding sites, an estrogen receptor half-site, and two AP-1 sites within the promoter region. 5'-RACE experimentsdetermined the transcription start site to be located 82 bp upstream of the ATG translation start codon. Electrophoretic mobility shift, assays and supershift analysis demonstrated SF-1 binding to three SF-1 binding sites in the rat StAR promoter with high affinity and two SF-1 binding sites with low affinity. Transfection of mouse Y1 adrenal tumor cells and human bladder carcinoma cells (HTB9s) with the rat StAR promoter demonstrated that SF-1 was able to activate transcription of the luciferase reporter gene and that the rat StAR promoter was responsive to cAMP. Nested deletions of the rat StAR promoter (1.9 kb) identified a region between - 1413 and -998 that is essential for maximal activation of the rat StAR gene in HTB9 cells; however, deletion of this region does not affect responsiveness to cAMP. 5'-Deletion and site-directed mutagenesis experiments demonstrated that the SF-1 motifs identified within the rat StAR promoter (located at positions -764, -455, and - 106) were sufficient to activate transcription as well as confer cAMP responsiveness to the rat StAR gene. Site-directed mutagenesis studies using the smallest promoter fragment demonstrated that the two proximal SF-1 binding sites are crucial for StAR gene transcription, both at a basal level and in response to cAMP stimulation. These studiesprovide novel insights into the regulation of the rat StAR gene at the transcriptional level by SF-1.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/09/20 alle ore 07:35:26