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Submitted on March 2, 2004
Accepted on October 1, 2004
Deptartment of Pediatrics and The Metabolic Research Unit, University of California, San Francisco, San Francisco, California 94143-0978
* To whom correspondence should be addressed. E-mail: wlmlab{at}itsa.ucsf.edu.
The cholesterol side-chain cleavage enzyme, P450scc, initiates biosynthesis of all steroid hormones. Adrenal and gonadal P450scc expression requires SF1, but P450scc expression in human placental JEG-3 cells utilizes an SF1-independent element at -155/-131 that is inactive in adrenals and gonads. We previously cloned two transcription factors, LBP-1b and LBP-9, from JEG-3 cells. In transient transfection assays, LBP-1b activated the -155/-131 element whereas LBP-9 suppressed its LBP-1b-stimulated expression. To assess the roles of these factors on the intact P450scc gene, we stably expressed LBP-1b or LBP-9 in JEG-3 cells. All cell lines stably expressing LBP-1b-EGFP increased P450scc expression, but cell lines stably expressing LBP-9-EGFP either increased or decreased P450scc expression. 8-Br-cAMP induced endogenous LBP-9, but not LBP-1b expression. GST pull-downs showed that LBP-1b and LBP-9 can dimerize with themselves and with each other; LBP-1b residues 300-540 and LBP-9 residues 300-479 were required for dimer formation. GST pull-downs, bandshifts and transient transfection assays showed that TReP-132 (another factor that can bind to -155/-131) does not interact with either LBP-1b or LBP-9, nor influence their ability to induce or suppress transcription from the -155/-131 element. Gal4 transactivation assays showed that transcriptional repression activity by LBP-9 requires residues 100-200. RNAi knockdown of either LBP-1b or LBP-9 mRNAs decreased P450scc expression. LBP-1b is an important SF1-independent transcriptional activator stimulating P450scc expression in human placental JEG-3 cells, whereas LBP-9 modulates the action of LBP-1b, exerting both positive and negative effects.
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