STRUCTURE OF THE HUMAN STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR) GENE - STAR STIMULATES MITOCHONDRIAL CHOLESTEROL 27-HYDROXYLASE ACTIVITY

Steroidogenic acute regulatory protein (StAR) plays a key role in ster oid hormone synthesis by enhancing the metabolism of cholesterol into pregnenolone. We determined the organization of the StAR structural ge ne, mapped to 8p11.2. The gene spans 8 kb and consists of seven exons interrupted by six introns. The 1.3 kb of DNA upstream from the transc ription start site directed expression of a luciferase reporter gene i n mouse Y-1 adrenal cortical tumor cells but not in BeWo choriocarcino ma cells. Reporter gene expression in the Y-1 cells was increased more than 2-fold by 8-Br-cAMP, indicating that the 1.3 kb DNA fragment con tains sequences that confer tissue-specific expression and cAMP regula tion. The sequence of a related StAR pseudogene, mapped to chromosome 13, lacks introns and has an insertion, numerous substitutions, and de letions. Expression of StAR in COS-1 cells cotransfected with choleste rol 27-hydroxylase (P450c27) and adrenodoxin resulted in a 6-fold incr ease in formation of 3 beta-hydroxy-5-cholestenoic acid, demonstrating that StAR's actions an not specific to steroidogenesis but extend to other mitochondrial cholesterol-metabolizing enzymes.