ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes

Lee, Seung Yon; Park, Eunsook; Kim, Seung-Chang; Ahn, Ryun Sup; Ko, Che Myong; Lee, Keesook

doi:10.1016/j.mce.2012.05.015

Cited by 22 publications

(19 citation statements)

References 73 publications

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“…Mouse Leydig tumor MA-10 cells were kindly provided by Dr. M. Ascoli (University of Iowa, Iowa) and maintained in RPMI 1640 medium (HyClone, Logan, Utah) supplemented with 15% horse serum (Gibco, Carlsbad, CA) and antibiotics [31]. Rat Leydig tumor R2C cells were purchased from ATCC (Manassas, VA) and maintained in F10 medium supplemented with 15% horse serum, 2.5% fetal bovine serum (FBS, HyClone) and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

“…Preparation of mouse Leydig cells was carried out as previously described [31]. Briefly, the mice at 12 weeks were sacrificed by cervical dislocation and testes were collected.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was conducted as previously described [31]. The nuclear/cytosol fractionation kit (Bio Vision Technology Inc., Canada) was used to separate nuclear and cytoplasmic proteins, according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…The cells were then processed for ChIP assays as previously described [31]. Anti-Nur77 antibody (sc-5569, Santa Cruz Biotechnology) was used for immunoprecipitation.…”

Section: Methodsmentioning

confidence: 99%

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Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

et al. 2014

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Transforming growth factor- β1 (TGF-β1) has been reported to inhibit luteinizing hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the mechanism by which TGF-β1 controls the steroidogenesis in Leydig cells is not well understood. Here, we investigated the possibility that TGF-β1 represses steroidogenesis through cross-talk with the orphan nuclear receptor Nur77. Nur77, which is induced by LH/cAMP signaling, is one of major transcription factors that regulate the expression of steroidogenic genes in Leydig cells. TGF-β1 signaling inhibited cAMP-induced testosterone production and the expression of steroidogenic genes such as P450c17, StAR and 3β-HSD in mouse Leydig cells. Further, TGF-β1/ALK5 signaling repressed cAMP-induced and Nur77-activated promoter activity of steroidogenic genes. In addition, TGF-β1/ALK5-activated Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by interfering with Nur77 binding to DNA. In primary Leydig cells isolated from Tgfbr2flox/flox Cyp17iCre mice, TGF-β1-mediated repression of cAMP-induced steroidogenic gene expression was significantly less than that in primary Leydig cells from Tgfbr2flox/flox mice. Taken together, these results suggest that TGF-β1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via the suppression of Nur77 transactivation in testicular Leydig cells. These findings may provide a molecular mechanism involved in the TGF-β1-mediated repression of testicular steroidogenesis.

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Section: Methodsmentioning

confidence: 99%

“…Preparation of mouse Leydig cells was carried out as previously described [31]. Briefly, the mice at 12 weeks were sacrificed by cervical dislocation and testes were collected.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The cells were then processed for ChIP assays as previously described [31]. Anti-Nur77 antibody (sc-5569, Santa Cruz Biotechnology) was used for immunoprecipitation.…”

Section: Methodsmentioning

confidence: 99%

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Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

et al. 2014

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“…The ERaf/f CYP17iCre mouse testis has normal seminiferous histology at 3-16 mo of age, and these mice present with normal T levels until 12 mo of age; T levels increase significantly at 16 mo of age [82]. In the ERaf/f CYP17iCre mouse testis, StAR mRNA levels are significantly higher compared with WT mice at 3-16 mo of age, 17b-HSD3 mRNA levels are significantly higher at 12 mo of age, and LHR mRNA levels are significantly higher at 16 mo of age [82]. It would be of great interest to have a better characterization of and more experimental functional data on the testicular phenotype of this ERaf/f CYP17iCre model.…”

Section: Tissue-specific Er Ko and Knock-in Micementioning

confidence: 99%

Oestrogen action and male fertility: experimental and clinical findings

Jia

et al. 2015

Cell. Mol. Life Sci.

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A proper balance between androgen and oestrogen is fundamental for normal male reproductive development and function in both animals and humans. This balance is governed by the cytochrome P450 aromatase, which is expressed also under spatio-temporal control. Oestrogen receptors ERα and/or ERβ, together with the membrane-associated G-protein-coupled functional ER (GPER), mediate the effects of oestrogen in the testis. Oestrogen action in male reproduction is more complex than previously predicted. The androgen/oestrogen balance and its regulation in the masculinisation programming window (MPW) during foetal life is the most critical period for the development of the male reproductive system. If this balance is impaired during the MPW, the male reproductive system may be negatively affected. Recent data from genetically modified mice and human infertile patients have shown that oestrogens may promote the engulfment of live Leydig cells by macrophages leading to male infertility. We also discuss recent data on environmental oestrogen exposure in men and rodents, where a rodent-human distinction is crucial and analyse some aspects of male fertility potentially related to impaired oestrogen/androgen balance.

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17β-Estradiol Delays 6-OHDA-Induced Apoptosis by Acting on Nur77 Translocation from the Nucleus to the Cytoplasm

et al. 2013

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Nuclear receptors (Nurs) represent a large family of gene expression regulating proteins. Gathering evidence indicates an important role for Nurs as transcription factors in dopamine neurotransmission. Nur77, a member of the Nur superfamily, plays a role in mediating the effects of antiparkinsonian and neuroleptic drugs. Besides, Nur77 survival and apoptotic roles depend largely on its subcellular localization. Estrogens are known for their neuroprotective properties, as demonstrated in animal and clinical studies. However, their action on Nur77 translocation pertaining to neuroprotection has not been investigated yet. The aim of our study was to perform a kinetic study on the effect of neurotoxic 6-hydroxydopamine (6-OHDA) and 17β-estradiol (E2) on the subcellular localization of Nur77 with reference to the modulation of apoptosis in PC12 cells. Our results demonstrate that E2 administration alone does not affect Nur77 cytoplasmic/nuclear ratio, mRNA levels, or apoptosis in PC12 cells. The neurotoxin 6-OHDA significantly enhances cytoplasmic localization of Nur77 after merely 3 h, while precipitating apoptosis. 6-OHDA also increases Nur77 transcription, which could partly explain the rise in cytoplasmic localization of the protein. Finally, treatment with both E2 and 6-OHDA delays Nur77 accumulation in the cytoplasm and delays cell death for a few hours in our cellular paradigm. Pre-treatment with E2 does not alter the increase in levels of Nur77 mRNA produced by 6-OHDA, suggesting that a raise in nuclear translocation is likely responsible for the stabilization of the cytoplasmic/nuclear ratio until 6 h. These results suggest an intriguing cooperation between E2 and Nur77 toward cellular fate guidance.

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ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes

Cited by 22 publications

References 73 publications

Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

Oestrogen action and male fertility: experimental and clinical findings

17β-Estradiol Delays 6-OHDA-Induced Apoptosis by Acting on Nur77 Translocation from the Nucleus to the Cytoplasm

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