Effects of Smad3 on the proliferation and steroidogenesis in human ovarian luteinized granulosa cells

Liu, Yuxia; Chen, Xi; Xue, Xinying; Shen, Chunyan; Shi, Cheng-Min; Dong, Jian; Zhang, Hongquan; Liang, Rong; Li, Sen; Xu, Jian

doi:10.1002/iub.1280

Cited by 17 publications

(19 citation statements)

References 42 publications

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“…11 In this study, we showed that TGF- β signaling enhanced FSHR expression and its intracellular signaling, consistent with previous reports in other mammals. 11, 12, 48 Addition of TGF- β increased FSHR mRNA expression in a time-dependent manner in rat GCs, 48 whereas TGF- β 1 in the presence of FSH decreased FSHR expression in bovine GCs. 14 SMAD3, a core component of TGF- β signaling, is a signaling intermediate for TGF- β .…”

Section: Discussionsupporting

confidence: 92%

“…8 In this study, we further demonstrated that FSHR can control pGC apoptosis and follicular atresia. Moreover, silencing of FSHR decreased the levels of its intracellular signaling molecules such as PKA, 11 AKT, 30 and p-AKT in pGCs. In GCs, binding of FSH leads to the activation of FSHR, which can activate intracellular signaling.…”

Section: Discussionmentioning

confidence: 96%

“…Activation of FSHR signaling strengthens GC proliferation and function, 11, 18, 28 whereas silencing of FSHR signaling weakens GC proliferation and function. 29, 30 Our previous study showed that FSHR is downregulated during porcine follicular atresia.…”

Section: Discussionmentioning

confidence: 99%

“…9, 10 However, the mechanisms by which TGF- β signaling regulates pGC apoptosis remain unexplored. In ovarian GCs of other mammals, such as humans, 11 mice, 12 rats, 13 and cows, 14 TGF-β signaling is involved in FSHR expression and FSHR-induced cell function. Consistent with previous reports in mammals, TGF- β signaling cooperates with FOXL2 to regulate FSHR expression and GC function in pre-hierarchical follicles of hens.…”

mentioning

confidence: 99%

“…Furthermore, we aimed to determine whether TGF- β signaling is involved in the regulation of FSHR expression in pGCs, as has been shown in other mammals, 11, 14 and the effect of miRNAs targeting FSHR in this process.…”

mentioning

confidence: 99%

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TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis

et al. 2016

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Follicle-stimulating hormone receptor (FSHR) and its intracellular signaling control mammalian follicular development and female infertility. Our previous study showed that FSHR is downregulated during follicular atresia of porcine ovaries. However, its role and regulation in follicular atresia remain unclear. Here, we showed that FSHR knockdown induced porcine granulosa cell (pGC) apoptosis and follicular atresia, and attenuated the levels of intracellular signaling molecules such as PKA, AKT and p-AKT. FSHR was identified as a target of miR-143, a microRNA that was upregulated during porcine follicular atresia. miR-143 enhanced pGC apoptosis by targeting FSHR, and reduced the levels of intracellular signaling molecules. SMAD4, the final molecule in transforming growth factor (TGF)-β signaling, bound to the promoter and induced significant downregulation of miR-143 in vitro and in vivo. Activated TGF-β signaling rescued miR-143-reduced FSHR and intracellular signaling molecules, and miR-143-induced pGC apoptosis. Overall, our findings offer evidence to explain how TGF-β signaling influences and FSHR signaling for regulation of pGC apoptosis and follicular atresia by a specific microRNA, miR-143.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis

et al. 2016

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Activation of TGF‐β1/Smad3 signaling pathway inhibits the development of ovarian follicle in polycystic ovary syndrome by promoting apoptosis of granulosa cells

Shen

Wang

2018

Journal Cellular Physiology

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Objective: To investigate the role of the transforming growth factor‐β1 (TGF‐β1)/Smad3 signaling pathway in development of ovarian follicle by promoting apoptosis of granulosa cells in polycystic ovary syndrome (PCOS). Methods A total of 54 female rats were obtained and randomly assigned into the PCOS (n = 27) and control groups ( n = 27). PCOS rat models were constructed using the dehydroepi‐androsterone method to observe ovarian morphology and ultrastructure. Chemiluminescence immunoassay was performed to detect the levels of luteinizing hormone, follicle stimulating hormone, estradiol, progesterone, and testosterone. The release of TGF‐β1 in follicular fluid and serum was tested by the enzyme‐linked immunosorbent assay. Results Expression of p‐Smad3 significantly increased in granulosa cells of PCOS group. In terms of the Smad2 protein, there was no significant difference between the PCOS and control group. In comparison to the control group, the number of normal secondary follicles and normal antral follicles were significantly decreased, whereas the number of hypogenetic secondary follicles undergoing atresia and antral follicles were significantly elevated in the PCOS group. Furthermore, the thickness of granulosa cells decreased and the apoptosis of granulosa cells increased in the PCOS group compared with the control one. Conclusion These results indicate that p‐Smad3 may have a close relationship with apoptosis of granulosa cells, the mechanism is that the TGF‐β1/Smad3 signaling pathway may inhibit development of ovarian follicle of PCOS by regulating the apoptosis of granulosa cells.

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TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state

Wang

et al. 2019

Journal Cellular Physiology

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Both TGF-β/SMAD4 signaling pathway and HAS2-HA system have been shown to control granulosa cell (GC) state in mammalian ovary. However, the regulatory relationship between TGF-β/SMAD4 signaling pathway and HA system in GCs is not well known. Here, we report that the TGF-β/SMAD4 signaling pathway activates the HAS2-HA system by binding directly to the HAS2 promoter, ultimately controlling the GC state via the CD44-Caspase3 axis. SMAD4-induced HAS2 expression, HAS2-driven HA secretion, and HAS2-mediated GC state (proliferation and apoptosis) by interacting directly with the promoter region of the HAS2 gene. The CD44-Caspase3 axis, located downstream of the HAS2-HA system, was also activated by SMAD4 and the TGF-β/SMAD4 signaling pathway. However, there was no feedback regulation of the TGF-β/SMAD4 signaling pathway by the HAS2-HA system in GCs. In addition, we found that miRNA-26b attenuated HAS2 expression via SMAD4-dependent and -independent mechanisms. Our findings provide compelling evidence that HAS2 is a direct transcriptional target of SMAD4. They also reveal a novel mechanism by which the TGF-β/SMAD4 signaling pathway controls the GC state and alters the structural components of GCs in porcine ovaries.

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Effects of Smad3 on the proliferation and steroidogenesis in human ovarian luteinized granulosa cells

Cited by 17 publications

References 42 publications

TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis

TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis

Activation of TGF‐β1/Smad3 signaling pathway inhibits the development of ovarian follicle in polycystic ovary syndrome by promoting apoptosis of granulosa cells

TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state

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