IRS2 depletion inhibits cell proliferation and decreases hormone secretion in mouse granulosa cells

Lei, Lanjie; Feng, Han; Cui, Qiuyan; Liao, Weifang; Liu, Hui; Guan, Gaopeng; Yang, Lei

doi:10.1262/jrd.2018-055

Cited by 16 publications

(15 citation statements)

References 52 publications

(68 reference statements)

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“…Upon APC/C inactivation at the G1/S boundary, IRS2 is able to accumulate and stimulate 374 signaling required for normal progression through the latter stages of the cell cycle, 375 including the expression of proteins required for mitotic spindle checkpoint function. This 376 model is consistent with previous studies that implicate IRS2 in promoting the expression 377 of cell cycle-related genes, including mitotic cyclins (A and B) in mouse granulosa cells 378 (Lei et al, 2018). Furthermore, IR signal transduction promotes the expression of Plk1 (a 379 mitotic kinase) and CENP-A (a centromere protein) in β cells through a mechanism that 380 appears to depend on IRS2 rather than IRS1 (Folli et al, 2011;Shirakawa et al, 2017).…”

Section: Irs2 Expression Promotes a Functional Spindle Assembly Checksupporting

confidence: 84%

The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

Manohar

Gygi

et al. 2019

Preprint

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11Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling 12 downstream of the insulin receptor and other receptor tyrosine kinases. Transduction 13 through IRS2-dependent pathways is important for coordinating metabolic homeostasis, 14 and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the 15 importance of maintaining proper IRS2 abundance, little is known about what factors 16 mediate its protein stability. We conducted an unbiased proteomic screen to uncover 17 novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin 18 ligase that controls the abundance of key cell cycle regulators. Surprisingly, we found that 19 IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1. 20Consistent with the APC/C's role in degrading cell cycle regulators, we find that IRS2-null 21 cells are deficient in proteins involved in cell cycle progression and display spindle 22 assembly checkpoint defects during M-phase. Together, these findings reveal a new 23 pathway for IRS2 turnover and indicate that IRS2 is a critical component of the cell cycle 24control system in addition to acting as an essential metabolic regulator. 25 26

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Section: Irs2 Expression Promotes a Functional Spindle Assembly Checksupporting

confidence: 84%

The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

Manohar

Gygi

et al. 2019

Preprint

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“…Compared with the control treatment, PA treatment decreased E2 and P4 expression. The possible reason for the reductions could be the decreases in the levels of Star (the protein associated with the transport of cholesterol across the mitochondrial membrane), Cyp11a1 (the monooxygenase that catalyzes cholesterol and steroid synthesis), and Cyp19a1 (the enzyme responsible for androgen aromatization to estrogen) [31] shown in our results. Previous studies have demonstrated that E2 and P4 are indispensable for maintaining the normal physiological function of the ovary [44].…”

Section: Discussionmentioning

confidence: 99%

“…Immature female mice ( n = 285) were intraperitoneally injected with 8 IU pregnant mare serum gonadotrophin (PMSG) (Ningbo Sansheng, Ningbo, China) to facilitate granulosa cell proliferation. After 44 h, primary mouse granulosa cells were isolated and cultured as described previously [31]. Briefly, the ovaries were collected, and granulosa cells were released by puncturing the follicles with 26-gauge needles under sterile conditions.…”

Section: Methodsmentioning

confidence: 99%

Melatonin attenuates palmitic acid-induced mouse granulosa cells apoptosis via endoplasmic reticulum stress

et al. 2019

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Background Palmitic acid (PA), the main component of dietary saturated fat, causes apoptosis in many cell types, including mouse granulosa cell. Melatonin, an important endogenous hormone, has beneficial effects on female reproductive processes. Since elevated PA levels are present in follicular fluid (FF) of patients with infertility and are shown to be toxic for granulosa cells, we investigated the molecular mechanisms of PA toxicity in mouse granulosa cells and explored the effects of melatonin on PA-induced apoptosis. Methods Granulosa cells from immature female mice were cultured for 24 h in medium containing PA and/or melatonin. Then, the effects of PA alone or combined with melatonin on viability, apoptosis and endoplasmic reticulum (ER) stress in granulosa cells were detected by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry assay and western blot. After 48 h of PA and/or melatonin treatment, the concentrations of estradiol (E2) and progesterone (P4) in the culture supernatants were measured with ELISA kits. Results In this study, we explored the effects of melatonin on cell viability and apoptosis in PA-treated mouse granulosa cells and uncovered the signaling pathways involved in these processes. Our results showed that 200-800 μM PA treatment reduces cell viability, induces cell apoptosis, enhances the expression of apoptosis-related genes (Caspase 3 and B-cell lymphoma-2 (BCL-2) associated X protein (BAX)), and activates the expression of ER stress marker genes (glucose-regulated protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Melatonin treatment (1-10 μM) suppresses 400 μM PA-induced cell viability decrease, cell apoptosis, Caspase 3 activation, and BAX, CHOP, and GRP78 expression. In addition, we found that 10 μM melatonin successfully attenuated the 400 μM PA-induced estrogen (E2) and progesterone (P4) decreases. Conclusions This study suggests that PA triggers cell apoptosis via ER stress and that melatonin protects cells against apoptosis by inhibiting ER stress in mouse granulosa cells. Electronic supplementary material The online version of this article (10.1186/s13048-019-0519-z) contains supplementary material, which is available to authorized users.

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“…The IRS proteins are the classical substrates for insulin and IGF1 receptor tyrosine kinases, which play an important role in normal physiological activities [4]. IRS2 is known to mediate metabolic homeostasis [5] and plays an important role in ovarian functions [6]. Moreover, some studies have emphasized its role in growth and proliferation [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, some studies have emphasized its role in growth and proliferation [7,8]. In addition, IRS2 can also regulate cell functions, including cell survival, steroidogenesis, and cell differentiation through the PI3K/AKT signaling pathway [6].…”

Section: Introductionmentioning

confidence: 99%

miR-431 regulates granulosa cell function through the IRS2/PI3K/AKT signaling pathway

Yang

Liu

et al. 2020

Journal of Reproduction and Development

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MicroRNAs (miRNAs) regulate the functions of granulosa cells by interacting with their target mRNAs. Insulin receptor substrate 2 (IRS2) is one of the targets of miR-431 and can be regulated by ovarian hormones. However, the role of miR-431 and the associated signal transduction pathway in ovarian development has not been studied previously. In this study, we first analyzed the expression of miR-431 and IRS2 following stimulation with pregnant mare serum gonadotropin (PMSG) during the estrous cycle or different stages of ovarian development in mice. Subs equently, we investigated the role, function, and signaling pathway of miR-431 in the human granulosa cell line, COV434. The results showed that follicle stimulating hormone (FSH) gradually decreased miR-431 levels, induced IRS2, and promoted pAKT expression. Moreover, miR-431 overexpression and IRS2 knockdown attenuated AKT activation, inhibited cell proliferation, and decreased estradiol (E 2) and progesterone (P 4) synthesis. Further, luciferase reporter assay demonstrated that IRS2 was a direct target of miR-431. In conclusion, this study demonstrated that miR-431 regulates granulosa cell function through the IRS2/PI3K/AKT signaling pathway.

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IRS2 depletion inhibits cell proliferation and decreases hormone secretion in mouse granulosa cells

Cited by 16 publications

References 52 publications

The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

Melatonin attenuates palmitic acid-induced mouse granulosa cells apoptosis via endoplasmic reticulum stress

miR-431 regulates granulosa cell function through the IRS2/PI3K/AKT signaling pathway

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