Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

Yazawa, Takashi; Imamichi, Yoshitaka; Miyamoto, Kaoru; Khan, Muhammad Rafiullah; Uwada, Junsuke; Umezawa, Akihiro; Taniguchi, Tadatsugu

doi:10.2108/zs140237

Cited by 31 publications

(19 citation statements)

References 120 publications

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“…Thus, we added the mechanism of termination of LIM-HD transcriptional activities by direct degradation of LIM-HD transcription factors. It has been reported that NR5A1-the master regulator of steroidogenesis-can be ubiquitylated by the Skp1-Cullin-F-box (SCF) containing complex, a multisubunit RING-finger type E3 ligase (46). Of importance, Lhx9 is able to bind to and activate the NR5A1 promoter with its HD (12).…”

Section: Discussionmentioning

confidence: 99%

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Sun

Chu

et al. 2018

FASEB j.

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Testosterone is essential for spermatogenesis and the maintenance of secondary sexual characteristics in males. An important transcription factor, LIM-homeobox gene 9 (Lhx9) is indispensable for testis development and testosterone production; however, post-translational modifications of Lhx9 are largely unknown. Here, for the first time to our knowledge, we demonstrate that the level of Lhx9 protein increases in human chorionic gonadotropin-exposed Leydig cells and can be polyubiquitylated. We found that Smad ubiquitylation regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, targets Lhx9 for ubiquitin-mediated proteasome degradation, thereby negatively modulating its function. Increasing Smurf1 decreases the level of Lhx9 and inhibits the Lhx9 transactivation capacity of steroidogenic factor 1 [nuclear receptor subfamily 5, group A, member 1 (NR5A1)]. In contrast, the depletion of Smurf1 leads to increased expression of Lhx9 protein and enhances testosterone biosynthesis-related gene transcripts [NR5A1, steroidogenic acute regulatory protein, CYP17A1, hydroxy-δ-5-steroid dehydrogenase, hydroxy-δ-5-steroid dehydrogenase isomerase 6, and hydroxysteroid (17-β) dehydrogenase 3] and testosterone production in Leydig cells. Furthermore, we found that Smurf1 knockout mice exhibit higher levels of Lhx9 protein and steroidogenesis, which leads to increased serum testosterone concentration. These findings reveal that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly. Our results provide new insights into the molecular events that play a role in the homeostasis of testosterone levels and may provide a new target for testosterone regulation.-Hu, F., Zhu, Q., Sun, B., Cui, C., Li, C., Zhang, L. Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells.

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Section: Discussionmentioning

confidence: 99%

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Sun

Chu

et al. 2018

FASEB j.

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“…SF-1/Ad4BP is important for steroidogenesis by regulating the transcription of steroidogenesis-related genes, such as cytochrome P450 steroid hydroxylases, hydroxyl dehydrogenases, cholesterol deliverers and electron transporters [14]. In addition, because SF-1/Ad4BP-knockout mice fail to develop gonads and adrenal glands, SF-1/Ad4BP represents a master regulator of the development of these organs [13,[15][16][17].…”

Section: Development Of Steroidogenic Organsmentioning

confidence: 99%

“…In addition, because SF-1/Ad4BP-knockout mice fail to develop gonads and adrenal glands, SF-1/Ad4BP represents a master regulator of the development of these organs [13,[15][16][17]. SF-1/Ad4BP belongs to the nuclear hormone receptor (NR) 5A subfamily with liver receptor homolog-1 (LRH-1) [14,18,19]. Although LRH-1 is known to be abundantly expressed in tissues of endodermal origin (liver, pancreas and intestine), it is also expressed in adrenal glands and gonads.…”

Section: Development Of Steroidogenic Organsmentioning

confidence: 99%

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

et al. 2016

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Abstract. Steroid hormones are mainly produced in adrenal glands and gonads. Because steroid hormones play vital roles in various physiological processes, replacement of deficient steroid hormones by hormone replacement therapy (HRT) is necessary for patients with adrenal and gonadal failure. In addition to HRT, tissue regeneration using stem cells is predicted to provide novel therapy. Among various stem cell types, mesenchymal stem cells can be differentiated into steroidogenic cells following ectopic expression of nuclear receptor (NR) 5A subfamily proteins, steroidogenic factor-1 (also known as adrenal 4 binding protein) and liver receptor homolog-1, with the aid of cAMP signaling. Conversely, these approaches cannot be applied to pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, because of poor survival following cytotoxic expression of NR5A subfamily proteins. However, if pluripotent stem cells are first differentiated through mesenchymal lineage, they can also be differentiated into steroidogenic cells via NR5A subfamily protein expression. This approach offers a potential suitable cells for future regenerative medicine and gene therapy for diseases caused by steroidogenesis deficiencies. It represents a powerful tool to investigate the molecular mechanisms involved in steroidogenesis. This article highlights our own and current research on the induction of steroidogenic cells from various stem cells. We also discuss the future direction of their clinical application.Key words: Steroid hormone, Steroidogenic factor-1/adrenal 4 binding protein, Liver receptor homolog-1, Stem cells, Transcription STEROID hormones play essential roles in various physiological processes, such as glucose metabolism, stress response, fluid and electrolyte balance, sex differentiation, reproduction and sexual behavior. Steroid hormones are synthesized from cholesterol predominantly in the adrenal glands and gonads [1]. Dysfunction of these organs often cause deficiency in steroidogenesis, whereas patients suffer from painful and sometimes life-threatening conditions in the absence of hormone replacement [2][3][4][5][6]. Although hormone replacement therapy (HRT) well-established for treatment of these patients, the HRT is required throughout their life with the increased incidence of serious side effects. It is hoped that stem cell-based regenerative medicine will provide novel therapies for resolving these issues. Stem cell-derived steroidogenic cells could restore the normal function of intrinsic organs following their transplantation. Consequently, induction of steroidogenic cells from stem cells represents an essential first-step in achieving this therapeutic goal. In addition, stem cell-derived steroidogenic cells provide a powerful tool to study the development and function of steroidogenic cells, because they reflect the intrinsic cell's developmental processes and characteristics. In this article, we describe our research and that of other groups for the induction of steroidogenic c...

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“…Various transcription factors are involved in the regulation of gene expression by LH. Among them, steroidogenic factor‐1 (SF‐1)/adrenal 4 binding protein (Ad4BP)/NR5A1 is one of the most important transcription factors, which belong to the nuclear receptor superfamily (Parker & Schimmer, ; Schimmer & White, ; Yazawa et al, ). In Leydig cell‐specific SF‐1/Ad4BP knockout (KO) mice, expression of steroidogenesis‐related genes and production of androgen are markedly reduced in testis (Jeyasuria et al, ).…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase‐2 is acutely induced by CCAAT/enhancer‐binding protein β to produce prostaglandin E₂ and F_2α following gonadotropin stimulation in Leydig cells

Yazawa

Imamichi

Yuhki

et al. 2019

Molecular Reproduction Devel

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Cyclooxygenase 2 (COX‐2) is an inducible rate‐limiting enzyme for prostanoid production. Because COX‐2 represents one of the inducible genes in mouse mesenchymal stem cells upon differentiation into Leydig cells, we investigated COX‐2 expression and production of prostaglandin (PG) in Leydig cells. Although COX‐2 was undetectable in mouse testis, it was transiently induced in Leydig cells by human chorionic gonadotropin (hCG) administration. Consistent with the finding that Leydig cells expressed aldo‐keto reductase 1B7 (PGF synthase) and PGE synthase 2, induction of COX‐2 by hCG caused a marked increase in testicular PGF 2α and PGE 2 levels. Using mouse Leydig cell tumor‐derived MA‐10 cells as a model, it was indicated by reporter assays and electron mobility shift assays that transcription of the COX‐2 gene was activated by CCAAT/enhancer‐binding protein β (C/EBPβ) with cAMP‐stimulation. C/EBPβ expression was induced by cAMP‐stimulation, whereas expression of C/EBP homolog protein (CHOP) was robustly downregulated. Transfection of CHOP expression plasmid inhibited cAMP‐induced COX‐2 promoter activity. In addition, CHOP reduced constitutive COX‐2 expression in other mouse Leydig cell tumor‐derived TM3 cells. These results indicate that COX‐2 is induced in Leydig cells by activation of C/EBPβ via reduction of CHOP expression upon gonadotropin‐stimulation to produce PGF 2α and PGE 2.

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Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

Cited by 31 publications

References 120 publications

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

Cyclooxygenase‐2 is acutely induced by CCAAT/enhancer‐binding protein β to produce prostaglandin E₂ and F_2α following gonadotropin stimulation in Leydig cells

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Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

Cited by 31 publications

References 120 publications

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

Cyclooxygenase‐2 is acutely induced by CCAAT/enhancer‐binding protein β to produce prostaglandin E2 and F2α following gonadotropin stimulation in Leydig cells

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Cyclooxygenase‐2 is acutely induced by CCAAT/enhancer‐binding protein β to produce prostaglandin E₂ and F_2α following gonadotropin stimulation in Leydig cells