This Article Full Text Full Text (PDF) All Versions of this Article: 18/2/279    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bassett, M. H. Articles by Rainey, W. E. Search for Related Content PubMed PubMed Citation Articles by Bassett, M. H. Articles by Rainey, W. E.

The Orphan Nuclear Receptors NURR1 and NGFIB Regulate Adrenal Aldosterone Production

Divisions of Reproductive and Pediatric Endocrinology (M.H.B., P.C.W., W.E.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032; and Department of Pathology (T.S., H.S.), Tohoku University School of Medicine, Sendai, Miyagi-ken 980-8575, Japan

Address all correspondence and requests for reprints to: William E. Rainey, Ph.D, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9032. 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 nerve growth factor-induced clone B (NGFIB) (NR4A1), Nur-related factor 1 (NURR1) (NR4A2), and steroidogenic factor-1 (SF-1) (NR5A1) on transcription of human CYP11B2 (hCYP11B2) and hCYP11B1 (11ß-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 (Ang) 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. EMSAs 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 calmodulin kinase inhibitor KN93 partially blocked K⁺-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of Ang II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5, and Ad1/cAMP response element (CRE) cis-elements reduced both basal and Ang 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 Ang II.

NURSA Molecule Pages Link:

Nuclear Receptors:   NGFIB  |  NURR1  |  SF-1

Ligands:   Aldosterone

This article has been cited by other articles:

				L. J. Martin, N. Boucher, C. Brousseau, and J. J. Tremblay The Orphan Nuclear Receptor NUR77 Regulates Hormone-Induced StAR Transcription in Leydig Cells through Cooperation with Ca2+/Calmodulin-Dependent Protein Kinase I Mol. Endocrinol., September 1, 2008; 22(9): 2021 - 2037. [Abstract] [Full Text] [PDF]

				X. Rui, J. Tsao, J. O. Scheys, G. D. Hammer, and B. P. Schimmer Contributions of Specificity Protein-1 and Steroidogenic Factor 1 to Adcy4 Expression in Y1 Mouse Adrenal Cells Endocrinology, July 1, 2008; 149(7): 3668 - 3678. [Abstract] [Full Text] [PDF]

				J. H. Jeon, K.-y. Kim, J. H. Kim, A. Baek, H. Cho, Y. H. Lee, J. W. Kim, D. Kim, S. H. Han, J.-S. Lim, et al. A novel adipokine CTRP1 stimulates aldosterone production FASEB J, May 1, 2008; 22(5): 1502 - 1511. [Abstract] [Full Text] [PDF]

				D. G. Romero, M. W. Plonczynski, B. L. Welsh, C. E. Gomez-Sanchez, M. Y. Zhou, and E. P. Gomez-Sanchez Gene expression profile in rat adrenal zona glomerulosa cells stimulated with aldosterone secretagogues Physiol Genomics, December 19, 2007; 32(1): 117 - 127. [Abstract] [Full Text] [PDF]

				E. F Nogueira, C. A Vargas, M. Otis, N. Gallo-Payet, W. B Bollag, and W. E Rainey Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells J. Mol. Endocrinol., December 1, 2007; 39(6): 365 - 374. [Abstract] [Full Text] [PDF]

				V. E. Beshay, J. C. Havelock, R. Sirianni, P. Ye, T. Suzuki, W. E. Rainey, and B. R. Carr The Mechanism for Protein Kinase C Inhibition of Androgen Production and 17{alpha}-Hydroxylase Expression in a Theca Cell Tumor Model J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4802 - 4809. [Abstract] [Full Text] [PDF]

				L. Lenzini, T. M. Seccia, E. Aldighieri, A. S. Belloni, P. Bernante, L. Giuliani, G. G. Nussdorfer, A. C. Pessina, and G. P. Rossi Heterogeneity of Aldosterone-Producing Adenomas Revealed by a Whole Transcriptome Analysis Hypertension, December 1, 2007; 50(6): 1106 - 1113. [Abstract] [Full Text] [PDF]

				D. G. Romero, S. Rilli, M. W. Plonczynski, L. L. Yanes, M. Y. Zhou, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis Physiol Genomics, June 19, 2007; 30(1): 26 - 34. [Abstract] [Full Text] [PDF]

				K.-H. Song, Y.-Y. Park, H. J. Kee, C. Y. Hong, Y.-S. Lee, S.-W. Ahn, H.-J. Kim, K. Lee, H. Kook, I.-K. Lee, et al. Orphan Nuclear Receptor Nur77 Induces Zinc Finger Protein GIOT-1 Gene Expression, and GIOT-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor SF-1 via Recruitment of HDAC2 J. Biol. Chem., June 9, 2006; 281(23): 15605 - 15614. [Abstract] [Full Text] [PDF]

				K. C. Wade, S. H. Guttentag, L. W. Gonzales, K. L. Maschhoff, J. Gonzales, V. Kolla, S. Singhal, and P. L. Ballard Gene Induction during Differentiation of Human Pulmonary Type II Cells In Vitro Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 727 - 737. [Abstract] [Full Text] [PDF]

				V. R. Holla, J. R. Mann, Q. Shi, and R. N. DuBois Prostaglandin E2 Regulates the Nuclear Receptor NR4A2 in Colorectal Cancer J. Biol. Chem., February 3, 2006; 281(5): 2676 - 2682. [Abstract] [Full Text] [PDF]

				H. Tanahashi, T. Mune, Y. Takahashi, M. Isaji, T. Suwa, H. Morita, N. Yamakita, K. Yasuda, T. Deguchi, P. C. White, et al. Association of Lys173Arg Polymorphism with CYP11B2 Expression in Normal Adrenal Glands and Aldosterone-Producing Adenomas J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6226 - 6231. [Abstract] [Full Text] [PDF]

				M. H. Bassett, B. Mayhew, K. Rehman, P. C. White, F. Mantero, G. Arnaldi, P. M. Stewart, I. Bujalska, and W. E. Rainey Expression Profiles for Steroidogenic Enzymes in Adrenocortical Disease J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5446 - 5455. [Abstract] [Full Text] [PDF]

				I. Kurihara, H. Shibata, S. Kobayashi, N. Suda, Y. Ikeda, K. Yokota, A. Murai, I. Saito, W. E. Rainey, and T. Saruta Ubc9 and Protein Inhibitor of Activated STAT 1 Activate Chicken Ovalbumin Upstream Promoter-Transcription Factor I-mediated Human CYP11B2 Gene Transcription J. Biol. Chem., February 25, 2005; 280(8): 6721 - 6730. [Abstract] [Full Text] [PDF]

				L. J. Martin and J. J. Tremblay The Human 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Type 2 Promoter Is a Novel Target for the Immediate Early Orphan Nuclear Receptor Nur77 in Steroidogenic Cells Endocrinology, February 1, 2005; 146(2): 861 - 869. [Abstract] [Full Text] [PDF]

				Y. Wu, S. Ghosh, Y. Nishi, T. Yanase, H. Nawata, and Y. Hu The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge Endocrinology, January 1, 2005; 146(1): 237 - 246. [Abstract] [Full Text] [PDF]

				F. Q. Pirih, A. Tang, I. C. Ozkurt, J. M. Nervina, and S. Tetradis Nuclear Orphan Receptor Nurr1 Directly Transactivates the Osteocalcin Gene in Osteoblasts J. Biol. Chem., December 17, 2004; 279(51): 53167 - 53174. [Abstract] [Full Text] [PDF]

				D. G. Romero, M. Plonczynski, G. R. Vergara, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Angiotensin II early regulated genes in H295R human adrenocortical cells Physiol Genomics, September 16, 2004; 19(1): 106 - 116. [Abstract] [Full Text] [PDF]

				M. H. Bassett, T. Suzuki, H. Sasano, C. J. M. de Vries, P. T. Jimenez, B. R. Carr, and W. E. Rainey The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3{beta}-Hydroxysteroid Dehydrogenase: IMPLICATIONS FOR THE CONTROL OF ADRENAL FUNCTIONAL ZONATION J. Biol. Chem., September 3, 2004; 279(36): 37622 - 37630. [Abstract] [Full Text] [PDF]

				L. Lu, T. Suzuki, Y. Yoshikawa, O. Murakami, Y. Miki, T. Moriya, M. H. Bassett, W. E. Rainey, Y. Hayashi, and H. Sasano Nur-Related Factor 1 and Nerve Growth Factor-Induced Clone B in Human Adrenal Cortex and Its Disorders J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4113 - 4118. [Abstract] [Full Text] [PDF]

				K.-H. Song, Y.-Y. Park, K. C. Park, C. Y. Hong, J. H. Park, M. Shong, K. Lee, and H.-S. Choi The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation Mol. Endocrinol., August 1, 2004; 18(8): 1929 - 1940. [Abstract] [Full Text] [PDF]