Cargando…
Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells
In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follic...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237239/ https://www.ncbi.nlm.nih.gov/pubmed/25321482 http://dx.doi.org/10.1038/cddis.2014.400 |
_version_ | 1782345312664289280 |
---|---|
author | Shen, M Liu, Z Li, B Teng, Y Zhang, J Tang, Y Sun, S-C Liu, H |
author_facet | Shen, M Liu, Z Li, B Teng, Y Zhang, J Tang, Y Sun, S-C Liu, H |
author_sort | Shen, M |
collection | PubMed |
description | In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follicular atresia and granulosa cell apoptosis. FSH inhibits the induction of FoxO1. In this report, we investigated the role of FSH-FoxO1 pathway in mouse follicular atresia. FSH dampened stress-induced apoptosis and the expression of FoxO1 and pro-apoptosis genes in mouse granulosa cells (MGCs). In contrast, overexpression of FoxO1 inhibited the viability of MGCs and induced the expression of endogenous FoxO1. The signaling cascades involved in regulating FoxO1 activity upon FSH treatment were identified using FSH signaling antagonists. Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH. Moreover, inhibition of PKA or PI3K impaired FSH-induced AKT activity, but inactivation of PI3K or AKT had little effect on PKA activity in the presence of FSH. Correspondingly, constitutive activation of FoxO1 (all three AKT sites were replaced by alanines) also promoted MGC apoptosis despite FSH administration. Furthermore, both luciferase reporter assays and chromatin immunoprecipitation assays showed that FoxO1 directly bound to a FoxO-recognized element site within the FoxO1 promoter and contributed to the regulation of FoxO1 expression in response to FSH. Taken together, we propose a novel model in which FSH downregulates FoxO1-dependent apoptosis in MGCs by coordinating the PKA–PI3K–AKT–FoxO1 axis and FoxO1–FoxO1 positive feedback. |
format | Online Article Text |
id | pubmed-4237239 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-42372392014-11-26 Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells Shen, M Liu, Z Li, B Teng, Y Zhang, J Tang, Y Sun, S-C Liu, H Cell Death Dis Original Article In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follicular atresia and granulosa cell apoptosis. FSH inhibits the induction of FoxO1. In this report, we investigated the role of FSH-FoxO1 pathway in mouse follicular atresia. FSH dampened stress-induced apoptosis and the expression of FoxO1 and pro-apoptosis genes in mouse granulosa cells (MGCs). In contrast, overexpression of FoxO1 inhibited the viability of MGCs and induced the expression of endogenous FoxO1. The signaling cascades involved in regulating FoxO1 activity upon FSH treatment were identified using FSH signaling antagonists. Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH. Moreover, inhibition of PKA or PI3K impaired FSH-induced AKT activity, but inactivation of PI3K or AKT had little effect on PKA activity in the presence of FSH. Correspondingly, constitutive activation of FoxO1 (all three AKT sites were replaced by alanines) also promoted MGC apoptosis despite FSH administration. Furthermore, both luciferase reporter assays and chromatin immunoprecipitation assays showed that FoxO1 directly bound to a FoxO-recognized element site within the FoxO1 promoter and contributed to the regulation of FoxO1 expression in response to FSH. Taken together, we propose a novel model in which FSH downregulates FoxO1-dependent apoptosis in MGCs by coordinating the PKA–PI3K–AKT–FoxO1 axis and FoxO1–FoxO1 positive feedback. Nature Publishing Group 2014-10 2014-10-16 /pmc/articles/PMC4237239/ /pubmed/25321482 http://dx.doi.org/10.1038/cddis.2014.400 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0 |
spellingShingle | Original Article Shen, M Liu, Z Li, B Teng, Y Zhang, J Tang, Y Sun, S-C Liu, H Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title | Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title_full | Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title_fullStr | Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title_full_unstemmed | Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title_short | Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
title_sort | involvement of foxo1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237239/ https://www.ncbi.nlm.nih.gov/pubmed/25321482 http://dx.doi.org/10.1038/cddis.2014.400 |
work_keys_str_mv | AT shenm involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT liuz involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT lib involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT tengy involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT zhangj involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT tangy involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT sunsc involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells AT liuh involvementoffoxo1intheeffectsoffolliclestimulatinghormoneoninhibitionofapoptosisinmousegranulosacells |