https://scholars.lib.ntu.edu.tw/handle/123456789/459991
標題: | Iron suppresses ovarian granulosa cell proliferation and arrests cell cycle through regulating p38 mitogen-activated protein kinase/p53/p21 pathway | 作者: | MEI-JOU CHEN Chou C.-H CHIA-TUNG SHUN TSUI-LIEN MAO Wen W.-F CHIN-DER CHEN SHEE-UAN CHEN YU-SHIH YANG HONG-NERNG HO |
公開日期: | 2017 | 卷: | 97 | 期: | 3 | 起(迄)頁: | 438-448 | 來源出版物: | Biology of Reproduction | 摘要: | Iron is an essential nutrient that may exert toxic effects when it accumulates in tissues. Little is known regarding its effects on gonadal function. Both Fe2+ and Fe3+ could be released from iron deposition. We employed mouse nonluteinized granulosa cell for in vitro studies and human ovarian tissues for Prussian blue and immunohistochemical staining to identify the iron deposition and effect in vivo. After treatment with FeSO4-7H2O or FeCl3 in granulosa cell cultured with folliclestimulating hormone (FSH) for 48 h, we found that Fe2+ significantly suppressed FSH-induced granulosa cell proliferation and arrested the cell cycle at the G2/M phase by cell proliferation assay and flow cytometry. Fe2+ significantly increased intracellular reactive oxygen species (ROS) and ferritin levels of mouse granulosa cells. The increases in p21 and p53 messenger RNA and protein expression facilitated by Fe2+ treatment in mouse granulosa cells were significantly suppressed by separate treatments with p53 small interfering RNA and p38 mitogen-activated protein kinase (MAPK) inhibitors. An ROS inhibitor downregulated Fe2+-induced increases in p38MAPK expression in mouse granulosa cells. Quantitative analysis of immunohistochemical staining revealed that human ovarian tissue sections with positive Prussian blue staining had lower levels of proliferating cell nuclear antigen expression, but higher levels of p21, p53, and CDC25C expression than those with negative Prussian blue staining. Conclusively, Fe2+ could directly arrest the cell cycle and inhibit granulosa cell proliferation by regulating the ROS-mediated p38MAPK/p53/p21 pathway. Therefore, iron can directly affect female gonadal function. ? The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/459991 | ISSN: | 0006-3363 | DOI: | 10.1093/biolre/iox099 | SDG/關鍵字: | cycline; ferric ferrocyanide; ferric ion; ferritin; ferrous ion; follitropin; iron; messenger RNA; mitogen activated protein kinase p38; mitogen activated protein kinase p38 inhibitor; protein p21; protein p53; reactive oxygen metabolite; small interfering RNA; ferritin; follitropin; iron; mitogen activated protein kinase p38; p21 activated kinase; protein p53; reactive nitrogen species; small interfering RNA; animal cell; animal cell culture; animal experiment; antigen expression; Article; cell cycle arrest; cell proliferation; cell proliferation assay; female; ferritin blood level; flow cytometry; G2 phase cell cycle checkpoint; gonad function; granulosa cell; human; human tissue; immunohistochemistry; in vitro study; in vivo study; MAPK signaling; mouse; nonhuman; ovary tissue; priority journal; protein expression; quantitative analysis; animal; apoptosis; blood; cell cycle checkpoint; cell proliferation; cytology; drug effect; genetics; granulosa cell; Institute for Cancer Research mouse; metabolism; ovary; signal transduction; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Female; Ferritins; Follicle Stimulating Hormone; Granulosa Cells; Iron; Mice; Mice, Inbred ICR; Ovary; p21-Activated Kinases; p38 Mitogen-Activated Protein Kinases; Reactive Nitrogen Species; RNA, Small Interfering; Signal Transduction; Tumor Suppressor Protein p53 |
顯示於: | 醫學系 |
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