Heterogeneous Nuclear Ribonucleoprotein A2/B1 Regulates the Self-Renewal and Pluripotency of Human Embryonic Stem Cells Via the Control of the G1/S Transition

Authors

  • Hong Seo Choi,

    1. Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, Korea
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  • Hyun Min Lee,

    1. Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, Korea
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  • Young-Joo Jang,

    1. Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam, Korea
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  • Cheorl-Ho Kim,

    1. Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
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  • Chun Jeih Ryu

    Corresponding author
    1. Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, Korea
    • Ph.D., Institute of Bioscience, Department of Bioscience and Biotechnology, Sejong University, 98, Gunja-Dong, Gwangjin-Gu, Seoul 143-747, Korea. E-mail: cjryu@sejong.ac.kr Telephone: 82-2-3408-3718; Fax: 82-2-3408-4334;

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  • Author contributions: H.S.C.: collection of data and data interpretation; H.M.L. and Y.-J.J.: collection of data; C.-H.K.: data analysis; C.J.R.: conception and design, financial support, and manuscript writing.

Abstract

Self-renewal and pluripotency of human embryonic stem cells (hESCs) are a complex biological process for maintaining hESC stemness. However, the molecular mechanisms underlying these special properties of hESCs are not fully understood. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) is a multifunctional RNA-binding protein whose expression is related to cell proliferation and carcinogenesis. In this study, we found that hnRNP A2/B1 expression was localized to undifferentiated hESCs and decreased upon differentiation of hESCs. hnRNP A2/B1 knockdown reduced the number of alkaline phosphatase-positive colonies in hESCs and led to a decrease in the expression of pluripotency-associated transcription factors OCT4, NANOG, and SOX2, indicating that hnRNP A2/B1 is essential for hESC self-renewal and pluripotency. hnRNP A2/B1 knockdown increased the expression of gene markers associated with the early development of three germ layers, and promoted the process of epithelial-mesenchymal transition, suggesting that hnRNP A2/B1 is required for maintaining the undifferentiated and epithelial phenotypes of hESCs. hnRNP A2/B1 knockdown inhibited hESC proliferation and induced cell cycle arrest in the G0/G1 phase before differentiation via degradation of cyclin D1, cyclin E, and Cdc25A. hnRNP A2/B1 knockdown increased p27 expression and induced phosphorylation of p53 and Chk1, suggesting that hnRNP A2/B1 also regulates the G1/S transition of hESC cell cycle through the control of p27 expression and p53 and Chk1 activity. Analysis of signaling molecules further revealed that hnRNP A2/B1 regulated hESC proliferation in a PI3K/Akt-dependent manner. These findings provide for the first time mechanistic insights into how hnRNP A2/B1 regulates hESC self-renewal and pluripotency. STEM Cells 2013;31:2647–2658

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