Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity

Tomohiro Kabuta*, Takeshi Mitsui, Masaki Takahashi, Yuuki Fujiwara, Chihana Kabuta, Chiho Konya, Yukihiro Tsuchiya, Yusuke Hatanaka, Kenko Uchida, Hirohiko Hohjoh, Keiji Wada

*この研究の対応する著者

    研究成果: Article査読

    31 被引用数 (Scopus)

    抄録

    Dysregulation of cell proliferation and the cell cycle are associated with various diseases, such as cancer. Cyclin-dependent kinases (CDKs) play central roles in cell proliferation and the cell cycle. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in a restricted range of tissues, including the brain and numerous types of cancer. However, the molecular functions of UCH-L1 remain elusive. In this study, we found that UCH-L1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity. Using several mutants of UCH-L1, we showed that this enhancement is dependent upon interaction levels between UCH-L1 and CDKs but is independent of the known ubiquitin-related functions of UCH-L1. Gain- and loss-of-function studies revealed that UCH-L1 enhances proliferation of multiple cell types, including human cancer cells. Inhibition of the interaction between UCH-L1 and cell cycle-associated CDK resulted in the abolishment of UCH-L1-induced enhancement of cell proliferation. RNA interference of UCH-L1 reduced the growth of human xenograft tumors in mice. We concluded that UCH-L1 is a novel regulator of the kinase activities of CDKs. We believe that our findings from this study will significantly contribute to our understanding of cell cycle-associated diseases.

    本文言語English
    ページ(範囲)12615-12626
    ページ数12
    ジャーナルJournal of Biological Chemistry
    288
    18
    DOI
    出版ステータスPublished - 2013 5月 3

    ASJC Scopus subject areas

    • 生化学
    • 細胞生物学
    • 分子生物学

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