Insulin-like growth factor-I prevents hypoxia-inducible factor-1 alpha-dependent G1/S arrest by activating cyclin E/cyclin-dependent kinase2 via the phoshatidylinositol-3 kinase/AKT/forkhead box O1/Cdkn1b pathway in porcine granulosa cells†.

Abstract

As the follicle develops, the thickening of the granulosa compartment leads to progressively deficient supply of oxygen in granulosa cells (GCs) due to the growing distances from the follicular vessels. These conditions are believed to cause hypoxia in GCs during folliculogenesis. Upon hypoxic conditions, several types of mammalian cells have been reported to undergo cell cycle arrest. However, it remains unclear whether hypoxia exerts any impact on cell cycle progression of GCs. On the other hand, although the GCs may live in a hypoxic environment, their mitotic capability appears to be unaffected in growing follicles. It thus raises the question whether there are certain intraovarian factors that might overcome the inhibitory effects of hypoxia. The present study provides the first evidence suggesting that cobalt chloride (CoCl2)-mimicked hypoxia prevented G1-to-S cell cycle progression in porcine GCs. In addition, we demonstrated that the inhibitory effects of CoCl2 on GCs cell cycle are mediated through hypoxia-inducible factor-1 alpha/FOXO1/Cdkn1b pathway. Moreover, we identified insulin-like growth factor-I (IGF-I) as an intrafollicular factor required for cell cycle recovery by binding to IGF-I receptor in GCs suffering CoCl2 stimulation. Further investigations confirmed a role of IGF-I in preserving G1/S progression of CoCl2-treated GCs via activating the cyclin E/cyclin-dependent kinase2 complex through the phoshatidylinositol-3 kinase/protein kinase B (AKT)/FOXO1/Cdkn1b axis. Although the present findings were based on a hypoxia mimicking model by using CoCl2, our study might shed new light on the regulatory mechanism of GCs cell cycle upon hypoxic stimulation.

• Authors: Chengyu Li, Zhaojun Liu, Jiaqi Zhou, Xueqin Meng, Shuo Liu, Weijian Li, Xue Zhang, Jilong Zhou, Wang Yao, Chao Dong, Yan Cao, Rongyang Li, Baobao Chen, Aiwen Jiang, Yi Jiang, Caibo Ning, Fang Zhao, Yinghui Wei, Shao-Chen Sun, Jingli Tao, Wangjun Wu, Ming Shen, Honglin Liu
• Journal: Biology of reproduction (Biol Reprod) Vol. 102 Issue 1 Pg. 116-132 (02 12 2020) ISSN: 1529-7268 [Electronic] United States
• PMID: 31435642 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cyclin E
• Forkhead Box Protein O1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Cyclin-Dependent Kinase Inhibitor p27
• Cobalt
• Estradiol
• Insulin-Like Growth Factor I
• Follicle Stimulating Hormone
• Proto-Oncogene Proteins c-akt
• Cyclin-Dependent Kinase 2
• cobaltous chloride

Topics

• Animals
• Cell Cycle (drug effects, physiology)
• Cell Cycle Checkpoints (drug effects, physiology)
• Cell Hypoxia (drug effects, physiology)
• Cobalt (pharmacology)
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Estradiol (pharmacology)
• Female
• Follicle Stimulating Hormone (pharmacology)
• Forkhead Box Protein O1 (metabolism)
• Granulosa Cells (drug effects, metabolism)
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Insulin-Like Growth Factor I (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects, physiology)
• Swine