Involvement of the up-regulated FoxO1 expression in follicular granulosa cell apoptosis induced by oxidative stress.
Follicular atresia is common in female mammalian ovaries, where most follicles undergo degeneration at any stage of growth and development. Oxidative stress gives rise to triggering granulosa cell apoptosis, which has been suggested as a major cause of follicular atresia. However, the underlying mechanism by which the oxidative stress induces follicular atresia remains unclear. FoxO transcription factors are known as critical mediators in the regulation of oxidative stress and apoptosis. In this study, the involvement of FoxO1 in oxidative stress-induced apoptosis of mouse follicular granulosa cells (MGCs) was investigated in vivo and in vitro. It was observed that increased apoptotic signals correlated with elevated expression of FoxO1 in MGCs when mice were treated with the oxidant. Correspondingly, the expressions of FoxO1 target genes, such as proapoptotic genes and antioxidative genes, were also up-regulated. In primary cultured MGCs, treatment with H(2)O(2) led to FoxO1 nuclear translocation. Further studies with overexpression and knockdown of FoxO1 demonstrated the critical role of FoxO1 in the induction of MGC apoptosis by oxidative stress. Finally, inactivation of FoxO1 by insulin treatment confirmed that FoxO1 induced by oxidative stress played a pivotal role in up-regulating the expression of downstream apoptosis-related genes in MGCs. Our results suggest that up-regulation of FoxO1 by oxidative stress leads to apoptosis of granulosa cells, which eventually results in follicular atresia in mice.
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
Ming
M
Shen
Fei
F
Lin
Jiaqing
J
Zhang
Yiting
Y
Tang
Wei-Kang
WK
Chen
Honglin
H
Liu
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005496:Follicular Atresia / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006107:Granulosa Cells / Q000378:metabolism* / Q000502:physiology; D007328:Insulin / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009574:Nitro Compounds / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011422:Propionates / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D009574:Nitro Compounds; D016877:Oxidants; D011422:Propionates; D017382:Reactive Oxygen Species; C015392:3-nitropropionic acid