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

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)12615-12626
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume288
    Issue number18
    DOIs
    Publication statusPublished - 2013 May 3

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology

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    Kabuta, T., Mitsui, T., Takahashi, M., Fujiwara, Y., Kabuta, C., Konya, C., Tsuchiya, Y., Hatanaka, Y., Uchida, K., Hohjoh, H., & Wada, K. (2013). 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. Journal of Biological Chemistry, 288(18), 12615-12626. https://doi.org/10.1074/jbc.M112.435701