Apoptosis of ovarian granulosa cells: Correlation with the reduced activity of ERK-signaling module

Gebauer, Gerd; Peter, Augustine T.; Onésime, Djamila; Dhanasekaran, N.

doi:10.1002/(sici)1097-4644(19991215)75:4<547::aid-jcb1>3.0.co;2-5

Cited by 46 publications

(25 citation statements)

References 23 publications

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“…These findings suggest that ERK, p38, and JNK critically regulate the fate of granulosa cells. However, there are few reports, including ours, indicating the activation of MAPKs in these cells [3,4,[9][10][11][12][13].…”

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confidence: 61%

Cellular Functions of Mitogen-activated Protein Kinases and Protein Tyrosine Phosphatases in Ovarian Granulosa Cells

Tamura

Nakagawa

Shimizu

et al. 2004

Journal of Reproduction and Development

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Abstract.A number of endocrine and paracrine factors regulate the follicular growth and atresia, which are closely associated with granulosa cell survival and apoptosis. However, the molecular mechanisms underlying the intracellular events induced by these factors are poorly understood. Here, we describe the correlation of mitogen-activated protein kinase (MAPK) activities with granulosa cell survival and apoptosis, and the cellular functions of protein tyrosine phosphatases (PTPs) in these cells based on our recent data. MAPKs play key roles in various cellular responses because numerous extracellular stimuli are integrated into MAPKs. The protein phospho-Tyr level regulated by protein tyrosine kinases (PTKs) and PTPs is a major control mechanism for processes as diverse as cell survival, proliferation, differentiation, and metabolism. Although PTKs are critically involved in granulosa cell survival and proliferation, there are no reports indicating the roles of PTPs in the ovary except for ours. Information about MAPKs and PTPs in these cells will provide a basis for the understanding of the molecular mechanisms controlling the fate of follicles. Key words: Mitogen-activated protein kinase (MAPK), Protein tyrosine phosphatase (PTP), Granulosa cell, Apoptosis, Adenovirus (J. Reprod. Dev. 50: [47][48][49][50][51][52][53][54][55] 2004) ver 99% of ovarian follicles in mammals undergo a degenerative process called atresia, which is characterized by granulosa cell apoptosis [1,2]. In contrast, only a few follicles mature and reach ovulation under the cyclic gonadotropin stimulation. The selection of granulosa cell apoptosis or survival is a critical process in determining the fate of follicles. To date, a number of endocrine and paracrine factors have been shown as survival or apoptosis-inducing factors for these cells in vivo and in vitro [1,2], but the molecular mechanisms underlying the induced intracellular events are poorly understood. In this review, we describe the correlation of mitogenactivated protein kinase (MAPK) activities with granulosa cell survival and apoptosis, and the cellular functions of protein tyrosine phosphatases (PTPs) in granulosa cells based on our recent data [3][4][5]. Both MAPKs and PTPs are considered important regulators for granulosa cell survival, proliferation, differentiation and apoptosis as they are in other types of cells. Correlation of MAPK Activities with Granulosa Cell Survival and Apoptosis MAPK familyA vast number of extracellular stimuli are integrated into MAPKs that conversely affect many of the signaling pathways induced by these stimuli.

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confidence: 61%

Cellular Functions of Mitogen-activated Protein Kinases and Protein Tyrosine Phosphatases in Ovarian Granulosa Cells

Tamura

Nakagawa

Shimizu

et al. 2004

Journal of Reproduction and Development

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“…FSH has also been shown to activate ERK and p38 mitogen-activated protein kinase (MAPK) in granulose cells [42,43]. Choi et al [44] found that FSH and LH activated MAPK and PI3K in human OSE cell.…”

Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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“…Follicular atresia and luteolysis are generally considered to occur by apoptosis. Recent reports characterizing the molecular mechanisms underlying this process demonstrate the role of several factors, including intracellular calcium concentration, MAPK, adenosine triphosphatase and extracellular-signal regulated kinase (Gebauer et al 1999, Peluso et al 2001, Park et al 2003. The Fas/Fas ligand system has been identified as a mediator of granulosa cell apoptosis in the rat ovary (Hakuno et al 1996, Kim et al 1999, and treatment with monoclonal anti-human-Fas antibody induces apoptosis in cultured human granulosa/luteal cells (Quirk et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Haem oxygenase augments porcine granulosa cell apoptosis in vitro

Harada¹,

Koi²,

Kubota³

et al. 2004

Journal of Endocrinology

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Haem oxygenases produce carbon monoxide, which, like nitric oxide, is a gaseous messenger molecule that is one of several important survival factors in ovarian follicles. However, little is known about the expression and possible functions of these enzymes in granulosa cells. The purpose of this study was to investigate the expression and possible role of haem oxygenases in porcine granulosa cells (PGCs). We obtained frozen sections of porcine ovaries and PGCs from ovarian follicles of various sizes by needle aspiration, and examined the expression of haem oxygenase-1 (HO-1; inducible type) and HO-2 (constitutive type) in PGCs by immunohistochemistry, RT-PCR, western blotting and flow cytometry. Both types of haem oxygenase were identified in PGCs throughout follicular development, but HO-1 was expressed primarily in granulosa cells in atretic follicles. We also investigated the effect of haem oxygenases on apoptosis of granulosa cells (flow cytometry to detect subdiploid DNA fluorescence) and on expression of Fas ligand (quantitative analysis of western blotting and flow cytometry). In tightly bound PGCs, the mean proportion of apoptotic cells treated with 1 µM haemin (a haem oxygenase substrate) was approximately 1·7-fold greater than that in untreated controls, and zinc protoporphyrin IX (ZnPP IX; a haem oxygenase inhibitor) completely inhibited the increase in apoptosis induced by haemin in 24-h culture. Conversely, in weakly associated PGCs, the proportion of apoptotic cells was not altered by haemin. The quantity of Fas ligand protein was increased in a dose-dependent manner in tightly bound PGCs treated with haemin compared with controls, and the haemin-induced increase in Fas ligand protein was inhibited by ZnPP IX. Thus we identified inducible HO-1 and constitutive HO-2 in PGCs throughout follicular development, and we conclude that products of reactions catalysed by haem oxygenases are likely to be important autocrine/paracrine factors that regulate apoptosis in PGCs.

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Apoptosis of ovarian granulosa cells: Correlation with the reduced activity of ERK-signaling module

Cited by 46 publications

References 23 publications

Cellular Functions of Mitogen-activated Protein Kinases and Protein Tyrosine Phosphatases in Ovarian Granulosa Cells

Cellular Functions of Mitogen-activated Protein Kinases and Protein Tyrosine Phosphatases in Ovarian Granulosa Cells

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Haem oxygenase augments porcine granulosa cell apoptosis in vitro

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