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Titolo:
Unveiling the mechanism of action and regulation of the steroidogenic acute regulatory protein
Autore:
Kallen, CB; Arakane, F; Christensen, LK; Watari, H; Devoto, L; Strauss, JF;
Indirizzi:
Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA Ctr Res Reprod & Womens Hlth Philadelphia PA USA 19104 phia, PA 19104 USA Univ Penn, Med Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA UnivPenn Philadelphia PA USA 19104 & Gynecol, Philadelphia, PA 19104 USA
Titolo Testata:
MOLECULAR AND CELLULAR ENDOCRINOLOGY
fascicolo: 1-2, volume: 145, anno: 1998,
pagine: 39 - 45
SICI:
0303-7207(19981025)145:1-2<39:UTMOAA>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
STEROL CARRIER PROTEIN-2; SIDE-CHAIN CLEAVAGE; LIPOID ADRENAL-HYPERPLASIA; LEYDIG TUMOR-CELLS; CO-REPRESSOR; STAR GENE; PROMOTER ACTIVITY; CYCLIC-AMP; CHOLESTEROL; EXPRESSION;
Keywords:
steroidogenic acute regulatory protein; trophic hormones; protein kinase A;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Strauss, JF Ctra,es Reprod & Womens Hlth, 778 Clin Res Bldg,415 Curie Blvd, Philadelphi Ctr Res Reprod & Womens Hlth 778 Clin Res Bldg,415 Curie BlvdPhiladelphia PA USA 19104
Citazione:
C.B. Kallen et al., "Unveiling the mechanism of action and regulation of the steroidogenic acute regulatory protein", MOL C ENDOC, 145(1-2), 1998, pp. 39-45

Abstract

Stimulation of steroid-producing cells of the gonads and adrenals with trophic hormone (LH, and ACTH, respectively) produces a marked increase in steroid hormone synthesis within minutes. The rate-limiting step in this acutesteroidogenic response is the transport of cholesterol from the outer to the inner mitochondrial membrane, where the first committed step in steroid synthesis is performed by the side-chain cleavage enzyme system (P450scc), resulting in the production of pregnenolone. This process of cholesterol translocation is blocked by inhibitors of protein synthesis (i.e. cycloheximide) indicating that the effect of trophic hormones, acting through the intermediacy of cAMP, most likely involves the de novo synthesis of a protein that is rapidly inactivated. The recently identified steroidogenic acute regulatory protein (StAR) appears to be the most likely candidate for the labile protein: (1) StAR is synthesized in response to cAMP and the StAR preprotein disappears rapidly in the presence of inhibitors of protein synthesis;(2) StAR has an N-terminal targeting sequence that directs the protein to the mitochondria; and (3) StAR protein is expressed almost exclusively in steroid-producing cells, its presence is correlated with steroid hormone production, and lack of functional StAR causes the autosomal recessive diseasecongenital lipoid adrenal hyperplasia (lipoid CAH), characterized by markedly impaired gonadal and adrenal steroid hormone synthesis. We have demonstrated that StAR is a target for serine phosphorylation mediated by protein kinase A (PKA), a process that is essential to maximizing StAR activity. StAR import by mitochondria is not essential to its steroidogenesis enhancingactivity, and more likely, represents a means of rapidly inactivating StAR. Truncation mutations and site-directed mutations in StAR demonstrated that the C-terminus of the protein contains the functionally important domains. Further, we have demonstrated potent steroidogenic activity of recombinant StAR protein on isolated mitochondria from bovine corpus luteum using protein that lacks the mitochondrial targeting sequence. These observations confirm that StAR import is not essential for its steroidogenic activity and suggest that StAR acts directly on the outer mitochondrial membrane in the absence of intermediary cytosolic factors. More recently, we have found that StAR functions as a cholesterol transfer protein that does not require a protein receptor or co-factor, suggesting that StAR acts directly on lipidsof the outer mitochondrial membrane to promote cholesterol translocation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/09/20 alle ore 07:37:58