Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia.

Hakuno, Naomi; Koji, Takehiko; Yano, Tetsu; Kobayashi, Nobuyuki; Tsutsumi, Osamu; Taketani, Yuji; Nakane, Paul K.

doi:10.1210/endo.137.5.8612534

Cited by 181 publications

(116 citation statements)

References 40 publications

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“…28 In female gonads, we and others demonstrated that Fas is expressed on granulosa cells of various follicles and luteal cells. [31][32][33][34][35][36][37][38] A few reports showed Fas expression on oocytes, but we have not been able to confirm this. 32,38,39 The expression on granulosa and luteal cells suggests that Fas is involved in follicular atresia and luteolysis for the gonadal homeostasis of adult mice.…”

Section: Introductionmentioning

confidence: 87%

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

et al. 2003

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Kit and its ligand stem cell factor (SCF) play a fundamental role in hematopoiesis, melanogenesis and gametogenesis. Homozygous W v mutant mice with a mutation in kit show abnormalities in these cell lineages. Fas is a member of the death receptor family inducing apoptosis. In this study, we generated double-mutant mice (W v /W v :Fas À/À ) and analyzed histologically their reproductive organs. In testes and ovaries of the double-mutant mice, testicular germ cells and oocytes were detected, respectively, whereas the same-aged W v /W v mice contained neither cells. In addition, inhibition of Kit signals by administration of anti-Kit mAb, which induces degeneration of testicular germ cells in vivo in wild-type mice, did not cause degeneration in Fas-deficient mice. In testicular germ cells of W v /W v mutant mice, an increase of Fas expression was observed in spermatogonia. Further, in vitro treatment with SCF was shown to downregulate Fas on fibroblasts expressing exogenous Kit through activation of PI3-kinase/Akt. All the results clearly indicate that Fasmediated apoptosis is involved in germ cell degeneration accompanied by defects in Kit-mediated signals, and Kit signaling negatively regulates Fas-mediated apoptosis in vivo.

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Section: Introductionmentioning

confidence: 87%

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

et al. 2003

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“…After fixation with 4% paraformaldehyde in PBS, the staining with Hoechst 33342 was performed and the frequency of cells with nuclear fragmentation as an indicator of apoptosis was calculated. 32 …”

Section: Cell Culturementioning

confidence: 99%

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Tamaru

Hishikawa

Ejima

et al. 2004

Laboratory Investigation

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Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecular mechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expression patterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies and nonradioactive in situ hybridization with T-T dimerized synthetic oligonucleotide probes. We next compared the results with the expression of estrogen receptor (ER) a and b, proliferative activity and apoptotic frequency (TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ERpositive (MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In the surgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), while KGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis of both KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated with the expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNEL index, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detected only in ER a-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect of KGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate that ER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, in human breast cancer. Keywords: apoptosis; breast cancer; estrogen receptor; immunohistochemistry; in situ hybridization; keratinocyte growth factor; TUNEL staining Breast cancer is the most frequent malignant tumor of women in the USA and European countries. In Japan, the frequency of breast cancer has rapidly increased during the last decade, and currently approximately 20 000 women develop breast cancer per year. However, our knowledge of the development and progression of breast cancer is still largely limited. The proliferation and differentiation of breast cancer cells are influenced by estrogen, 1-3 which exerts its action through binding to estrogen receptor (ER). Currently, ER is categorized into two subtypes, ER a and b, and both are believed to act as an active transcription factor, which binds to a specific DNA segment such as the estrogen responsive element (ERE) and AP-1 site, to regulate the expression of a variety of genes. 4,5 The majority of human breast cancer cells express both ER a and ER b. 6 While ER a is regarded as an indicator of

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“…1b). Since it has been reported that IFN-␥ increases Fas expression in some cell types (8,40,41), we examined the effect of this cytokine alone and in combination with TNF-␣ on Sertoli cell Fas expression by Western blotting analysis. As shown in Fig.…”

Section: Fas Ag Is Present In Cultured Mouse Sertoli Cells and Its Exmentioning

confidence: 99%

TNF-α and IFN-γ Regulate Expression and Function of the Fas System in the Seminiferous Epithelium

Riccioli

Starace

D’Alessio

et al. 2000

The Journal of Immunology

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Sertoli cells have long been considered to be involved in the regulation of the immune response in the testis. More recently, the Fas system has been implicated in the maintenance of the immune privilege in the testis as well as in the regulation of germ cell apoptosis. However, the control of Fas and Fas ligand (FasL) expression in the testis remains unknown. In the present study, we demonstrate that cultured mouse Sertoli cells constitutively express a low level of membrane-bound Fas protein, but not a soluble form of Fas. Sertoli cells stimulated with TNF-α and IFN-γ markedly increase the expression of both soluble and membrane-bound Fas in a dose-dependent manner. The up-regulated membrane-bound Fas protein is functionally active because it induces a significant level of Sertoli cell death in the presence of Neuro-2a FasL+ effector cells. Interestingly, the soluble form of Fas, which is induced by the same cytokines but has an antiapoptotic effect, is also functional. In fact, conditioned media from TNF-α-stimulated Sertoli cell cultures inhibit Neuro-2a FasL+-induced cell death. Taken together, our data suggest a possible regulatory role of TNF-α and IFN-γ on Fas-mediated apoptosis in the testis through disruption of the balance between different forms of Fas.

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Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia.

Cited by 181 publications

References 40 publications

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

TNF-α and IFN-γ Regulate Expression and Function of the Fas System in the Seminiferous Epithelium

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