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Submitted on January 8, 2003
Accepted on November 20, 2003
1 Divisions of Reproductive and Pediatric Endocrinology, UT Southwestern Medical Center, Dallas, Texas. Department of Pathology, Tohoku University School of Medicine, Sendai, Miyagi-ken, Japan
* To whom correspondence should be addressed. E-mail: william.rainey{at}utsouthwestern.edu.
Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 (encoding aldosterone synthase). The effects of NGFIB (NR4A1), NURR1 (NR4A2) and SF-1 (NR5A1) on transcription of human (h) CYP11B2 and hCYP11B1 (11
-hydroxylase) were compared in human H295R adrenocortical cells. hCYP11B2 expression was increased by NGFIB and NURR1. Although hCYP11B1 was activated by SF-1, cotransfection with SF-1 inhibited activation of hCYP11B2 by NGFIB and NURR1. NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin II, the major regulator of hCYP11B2 expression in vivo. Sequential deletion and mutagenesis of the hCYP11B2 promoter identified two functional NGFIB Response Elements (NBREs), one located at -766/-759 (NBRE-1) and the previously studied Ad5 element at -129/-114. Electrophoretic mobility shift assays suggested that both elements bound NGFIB and NURR1. In human adrenals, NURR1 immunoreactivity was preferentially localized in the zona glomerulosa and to a lesser degree in the zona fasciculata whereas NGFIB was detected in both zones. The CaM kinase inhibitor KN93 partially blocked K+-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of angiotensin II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5 and Ad1/CRE cis-elements reduced both basal and angiotensin II-induced levels of hCYP11B2 demonstrating that all three elements are important for maximal transcriptional activity. Our results suggest that NGFIB and NURR1 are key regulators of hCYP11B2 expression and may partially mediate the regulation of hCYP11B2 by angiotensin II.
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