SMAD3 inhibits SF-1-dependent activation of the CYP17 promoter in H295R cells

Derebecka-Holysz, Natalia; Lehmann, Tomasz P.; Hołysz, Marcin; Trzeciak, Wiesław H.

doi:10.1007/s11010-007-9585-4

Cited by 11 publications

(11 citation statements)

References 32 publications

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“…It has been proved that TGF-β1 inhibits the promoter activity via the Smad2 signalling pathway in human trophoblast cells [44]. Moreover, the orphan receptor steroidogenic factor-1 (SF-1) binding site has been identified as the response element in the proximal promoter PII of the rat aromatase gene [45], and TGF-β1 has been proved to inhibit SF-1 expression both at the transcriptional and translational levels in the mouse adrenocortical cell Y-1 [46] and human adrenocortical cell H295R [47].…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

Liu

Wang

et al. 2013

PLoS ONE

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BackgroundBesides androgens, estrogens produced in Leydig cells are also crucial for mammalian germ cell differentiation. Transforming growth factor-β1 (TGF-β1) is now known to have multiple effects on regulation of Leydig cell function. The objective of the present study is to determine whether TGF-β1 regulates estradiol (E2) synthesis in adult rat Leydig cells and then to assess the impact of TGF-β1 on Cx43-based gap junctional intercellular communication (GJIC) between Leydig cells.Methodology/Principal FindingsPrimary cultured Leydig cells were incubated in the presence of recombinant TGF-β1 and the production of E2 as well as testosterone (T) were measured by RIA. The activity of P450arom was addressed by the tritiated water release assay and the expression of Cyp19 gene was evaluated by Western blotting and real time RT-PCR. The expression of Cx43 and GJIC were investigated with immunofluorescence and fluorescence recovery after photo-bleaching (FRAP), respectively. Results from this study show that TGF-β1 down-regulates the level of E2 secretion and the activity of P450arom in a dose-dependent manner in adult Leydig cells. In addition, the expression of Cx43 and GJIC was closely related to the regulation of E2 and TGF-β1, and E2 treatment in turn restored the inhibition of TGF-β1 on GJIC.ConclusionsOur results indicate, for the first time in adult rat Leydig cells, that TGF-β1 suppresses P450arom activity, as well as the expression of the Cyp19 gene, and that depression of E2 secretion leads to down-regulation of Cx43-based GJIC between Leydig cells.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

Liu

Wang

et al. 2013

PLoS ONE

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“…Therefore, the repression of the basal promoter activity of P450c17 with active ALK5 expression may be related to the inhibition of SF-1 and LRH-1 transactivation by ALK5 signaling. Consistent with this speculation, Smad3 has been reported to inhibit SF-1-induced P450c17 promoter activity in adrenocortical cells [44].…”

Section: Discussionsupporting

confidence: 57%

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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“…Moreover, TGF-β1 was confirmed to enhance SF1 (a nuclear receptor NR5A subfamily member) and LRH-1 (liver receptor homolog 1) expression in GCs treated with FSH [46]. However, in human adrenocortical cells, TGF-β1 suppresses endogenous SF1 levels and the overexpression of SMAD3 inhibits SF1 binding to the CYP17 promotor [47]. Additionally, SF1 was required for TGF-β3-induced CYP19A1 expression and E2 release, whilst TGF-β3 enhanced the binding of SF1 to the endogenous ovary-specific CYP19A1 type II promoter [48].…”

Section: Discussionmentioning

confidence: 99%

Transactivation of miR-202-5p by Steroidogenic Factor 1 (SF1) Induces Apoptosis in Goat Granulosa Cells by Targeting TGFβR2

Ding¹,

Jin²,

Wang

et al. 2020

Cells

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MicroRNAs play key roles during ovary development, with emerging evidence suggesting that miR-202-5p is specifically expressed in female animal gonads. Granulosa cells (GCs) are somatic cells that are closely related to the development of female gametes in mammalian ovaries. However, the biological roles of miR-202-5p in GCs remain unknown. Here, we show that miR-202-5p is specifically expressed in GCs and accumulates in extracellular vesicles (EVs) from large growth follicles in goat ovaries. In vitro assays showed that miR-202-5p induced apoptosis and suppressed the proliferation of goat GCs. We further revealed that miR-202-5p is a functional miRNA that targets the transforming growth factor-beta type II receptor (TGFβR2). MiR-202-5p attenuated TGF-β/SMAD signaling through the degradation of TGFβR2 at both the mRNA and protein level, decreasing p-SMAD3 levels in GCs. Moreover, we verified that steroidogenic factor 1 (SF1) is a transcriptional factor that binds to the promoters of miR-202 and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) through luciferase reporter and chromatin immunoprecipitation (ChIP) assays. That contributed to positive correlation between miR-202-5p and CYP19A1 expression and estradiol (E2) release. Furthermore, SF1 repressed TGFβR2 and p-SMAD3 levels in GCs through the transactivation of miR-202-5p. Taken together, these results suggest a mechanism by which miR-202-5p regulates canonical TGF-β/SMAD signaling through targeting TGFβR2 in GCs. This provides insight into the transcriptional regulation of miR-202 and CYP19A1 during goat ovarian follicular development.

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SMAD3 inhibits SF-1-dependent activation of the CYP17 promoter in H295R cells

Cited by 11 publications

References 32 publications

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

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

Transactivation of miR-202-5p by Steroidogenic Factor 1 (SF1) Induces Apoptosis in Goat Granulosa Cells by Targeting TGFβR2

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