2. Academic Validation
  3. RNA binding protein IGF2BP1 meditates oxidative stress-induced granulosa cell dysfunction by regulating MDM2 mRNA stability in an m6A-dependent manner

RNA binding protein IGF2BP1 meditates oxidative stress-induced granulosa cell dysfunction by regulating MDM2 mRNA stability in an m6A-dependent manner

  • Redox Biol. 2022 Sep 24;57:102492. doi: 10.1016/j.redox.2022.102492.
Hongbei Mu 1,  Siying Cai 1,  Xiaofei Wang 1,  Huiying Li 1,  Ling Zhang 2,  Huaibiao Li 3,  Wenpei Xiang 4
Affiliations

Affiliations

  • 1 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Wuhan Tongji Reproductive Medicine Hospital, 128 Sanyang Road, Wuhan 430013, China. Electronic address: Zhling312@163.com.
  • 3 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: lihuaibiao@hust.edu.cn.
  • 4 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Wuhan Tongji Reproductive Medicine Hospital, 128 Sanyang Road, Wuhan 430013, China. Electronic address: wpxiang2010@hust.edu.cn.
PMID: 36182806 DOI: 10.1016/j.redox.2022.102492
Abstract

Both genetic and microenvironmental detrimental factors are involved in ovarian dysfunction, leading to the increasing rate of involuntary childlessness in recent years. Oxidative stress (OS), which is characterized by the imbalance of redox system with redundant Reactive Oxygen Species (ROS) overwhelming the antioxidant defense, is regarded as one of the culprits of ovarian dysfunction. OS causes damage to various types of ovarian cells including granulosa cells (GCs), jeopardizing the ovarian microenvironment, disturbing follicular development and participating in various female reproductive disorders. However, the specific molecular pathological mechanisms underlying this process have not been fully elucidated. In this study, we found that 3-nitropropionic acid (3-NP) treatment led to significant IGF2BP1 downregulation via, at least partially, inducing ROS overproduction. IGF2BP1 regulates GCs viability, proliferation, cell cycle and cellular senescence by enhancing MDM2 mRNA stability in an m6A-dependant manner. IGF2BP1 overexpression partially rescued 3-NP induced GCs damages, while ectopically expressed MDM2 alleviated both 3-NP or IGF2BP1-knockdown induced GCs dysfunction. These results reveal an epigenetic molecular mechanism underlying OS-related GCs disorders, which may help to establish a novel potential clinical marker for predicting the GCs status as well as the follicular developmental potential.

Keywords

Cellular senescence; Granulosa cells; IGF2BP1; Oxidative stress; Reactive oxygen species; m(6)A modification.

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