Abstract
Ad4BP/SF-1 (NR5A1), a member of the nuclear receptor superfamily, is known to play crucial roles in the regulation of steroidogenesis in the gonads and adrenal cortex, and many studies have demonstrated that all steroidogenic genes are direct targets of Ad4BP/SF-1. In addition, in vivo KO studies demonstrated that no steroidogenic organs formed in gene-disrupted mice, strongly suggesting that Ad4BP/SF-1 is essential for the development of the gonads and adrenal gland. However, it remains unclear how Ad4BP/SF-1 regulates the development of the steroidogenic organs and which additional non-steroidogenic genes are targeted.
We surveyed the target genes of Ad4BP/SF-1 in steroidogenic cells by mRNA deep sequencing and ChIP-sequence analyses using an Ad4BP/SF-1 antibody. Nearly all genes in energy-producing glycolytic pathways were found to be regulated by Ad4BP/SF-1. We also showed that the key genes implicated in NADPH production are the direct targets. Since sufficient supplies of ATP and NADPH are necessary for cellular survival and production of steroids, Ad4BP/SF-1 possibly orchestrates tissue-specific steroidogenic pathway and these housekeeping metabolic pathways.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology. 2005;146:1018–24.
Hatano O, Takayama K, Imai T, Waterman MR, Takakusu A, Omura T, Morohashi K. Sex-dependent expression of a transcription factor, Ad4BP, regulating steroidogenic P-450 genes in the gonads during prenatal and postnatal rat development. Development. 1994;120:2787–97.
Hoivik EA, Lewis AE, Aumo L, Bakke M. Molecular aspects of steroidogenic factor 1 (SF-1). Mol Cell Endocrinol. 2010;315:27–39.
Morohashi K, Honda S, Inomata Y, Handa H, Omura T. A common trans-acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J Biol Chem. 1992;267:17913–9.
Val P, Lefrancois-Martinez AM, Veyssiere G, Martinez A. SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl Recept. 2003;1:8.
Morohashi K, Zanger UM, Honda S, Hara M, Waterman MR, Omura T. Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP. Mol Endocrinol. 1993;7:1196–204.
Clemens JW, Lala DS, Parker KL, Richards JS. Steroidogenic factor-1 binding and transcriptional activity of the cholesterol side-chain cleavage promoter in rat granulosa cells. Endocrinology. 1994;134:1499–508.
Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77:481–90.
Morohashi KI, Omura T. Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function. FASEB J. 1996;10:1569–77.
Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, Milbrandt J. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A. 1995;92:10939–43.
Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O, et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995;204:22–9.
Almeida MQ, Soares IC, Ribeiro TC, Fragoso MC, Marins LV, Wakamatsu A, Ressio RA, Nishi MY, Jorge AA, Lerario AM, Alves VA, Mendonca BB, Latronico AC. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J Clin Endocrinol Metab. 2010;95:1458–62.
Doghman M, Karpova T, Rodrigues GA, Arhatte M, De Moura J, Cavalli LR, Virolle V, Barbry P, Zambetti GP, Figueiredo BC, Heckert LL, Lalli E. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol. 2007;21:2968–87.
Sbiera S, Schmull S, Assie G, Voelker HU, Kraus L, Beyer M, Ragazzon B, Beuschlein F, Willenberg HS, Hahner S, Saeger W, Bertherat J, Allolio B, Fassnacht M. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J Clin Endocrinol Metab. 2010;95:E161–71.
Zubair M, Oka S, Parker KL, Morohashi K. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Mol Endocrinol. 2009;23:1657–67.
Rabinowitz JD, Kimball E. Acidic acetonitrile for cellular metabolome extraction from Escherichia coli. Anal Chem. 2007;79:6167–73.
Nathan C, Ding A. SnapShot: reactive oxygen intermediates (ROI). Cell. 2010;140:e952.
Pollak N, Dolle C, Ziegler M. The power to reduce: pyridine nucleotides—small molecules with a multitude of functions. Biochem J. 2007;402:205–18.
Morohashi K, Baba T, Tanaka M. Steroid hormones and the development of reproductive organs. Sex Dev. 2013;7:61–79.
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A. 2007;104:19345–50.
Labuschagne CF, JF N, vd B, Mackay GM, Vousden KH, Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 2014;7:1248–58.
Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR, Vokes NI, Feist AM, Vander Heiden MG, Metallo CM. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014;55:253–63.
Morohashi K. Gonadal and extragonadal functions of Ad4BP/SF-1: developmental aspects. Trends Endocrinol Metab. 1999;10:169–73.
Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Wong M, Bakke M, Zhao L, Frigeri C, Hanley NA, Stallings N, Schimmer BP. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res. 2002;57:19–36.
Takayama K, Morohashi K, Honda S, Hara N, Omura T. Contribution of Ad4BP, a steroidogenic cell-specific transcription factor, to regulation of the human CYP11A and bovine CYP11B genes through their distal promoters. J Biochem. 1994;116:193–203.
Baba T, Otake H, Sato T, Miyabayashi K, Shishido Y, Wang CY, Shima Y, Kimura H, Yagi M, Ishihara Y, Hino S, Ogawa H, Nakao M, Yamazaki T, Kang D, Ohkawa Y, Suyama M, Chung BC, Morohashi K. Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1. Nat Commun. 2014;5:3634.
Inoue M, Shima Y, Miyabayashi K, Tokunaga K, Sato T, Baba T, Ohkawa Y, Akiyama H, Suyama M, Morohashi K. Isolation and characterization of fetal Leydig progenitor cells of male mice. Endocrinology. 2016;157:1222–33.
Shima Y, Miyabayashi K, Haraguchi S, Arakawa T, Otake H, Baba T, Matsuzaki S, Shishido Y, Akiyama H, Tachibana T, Tsutsui K, Morohashi K. Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testes. Mol Endocrinol. 2013;27:63–73.
Shima Y, Matsuzaki S, Miyabayashi K, Otake H, Baba T, Kato S, Huhtaniemi I, Morohashi K. Fetal Leydig cells persist as an androgen-independent subpopulation in the postnatal testis. Mol Endocrinol. 2015;29:1581–93.
Li B, Baba T, Miyabayashi K, Sato T, Shima Y, Ichinose T, Miura D, Ohkawa Y, Suyama M, Morohashi KI. Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells. Endocr J. 2017;64:315–24.
Freeman DA, Ascoli M. Studies on the source of cholesterol used for steroid biosynthesis in cultured Leydig tumor cells. J Biol Chem. 1982;257:14231–8.
Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988;9:295–318.
Fayard E, Auwerx J, Schoonjans K. LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends Cell Biol. 2004;14:250–60.
Wilson TE, Fahrner TJ, Johnston M, Milbrandt J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science. 1991;252:1296–300.
Charest-Marcotte A, Dufour CR, Wilson BJ, Tremblay AM, Eichner LJ, Arlow DH, Mootha VK, Giguere V. The homeobox protein Prox1 is a negative modulator of ERR{alpha}/PGC-1{alpha} bioenergetic functions. Genes Dev. 2010;24:537–42.
Chaveroux C, Eichner LJ, Dufour CR, Shatnawi A, Khoutorsky A, Bourque G, Sonenberg N, Giguere V. Molecular and genetic crosstalks between mTOR and ERRalpha are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab. 2013;17:586–98.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Nature Singapore Pte Ltd
About this chapter
Cite this chapter
Morohashi, Ki., Inoue, M., Li, B., Baba, T. (2018). Regulation of Metabolic Pathways in Steroidogenic Cells by Ad4BP/SF-1. In: Katabuchi, H., Ohba, T., Motohara, T. (eds) Cell Biology of the Ovary. Springer, Singapore. https://doi.org/10.1007/978-981-10-7941-2_3
Download citation
DOI: https://doi.org/10.1007/978-981-10-7941-2_3
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-10-7940-5
Online ISBN: 978-981-10-7941-2
eBook Packages: MedicineMedicine (R0)