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RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene

  1. Author:
    Brauweiler, A.
    Lorick, K. L.
    Lee, J. P.
    Tsai, Y. C.
    Chan, D.
    Weissman, A. M.
    Drabkin, H. A.
    Gemmill, R. M.

  2. Author Address

    Univ Colorado Denver & Hlth Sci Ctr, Div Med Oncol, Dept Med, Aurora, CO 80045 USA. Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. NCI, Lab Prot Dynam & Signaling, Frederick, MD 21701 USA.;Gemmill, RM, Univ Colorado Denver & Hlth Sci Ctr, Div Med Oncol, Dept Med, 12801 E 17th Ave,Mail Stop 8117,POB 6511, Aurora, CO 80045 USA.;robert.gemmill@uchsc.edu
    1. Year: 2007
    2. Date: Apr
  2. Journal: Oncogene
    1. 26
    2. 16
    3. Pages: 2263-2271
  4. Type of Article: Article
  5. ISSN: 0950-9232
  1. Abstract:

    TRC8/RNF139 and von Hippel-Lindau (VHL) both encode E3 ubiquitin (Ub) ligases mutated in clear-cell renal carcinomas (ccRCC). VHL, inactivated in nearly 70% of ccRCCs, is a tumor suppressor encoding the targeting subunit for a Ub ligase complex that down-regulates hypoxia-inducible factor-alpha. TRC8/RNF139 is a putative tumor suppressor containing a sterol-sensing domain and a RING-H2 motif essential for Ub ligase activity. Here we report that human kidney cells are growth inhibited by TRC8. Inhibition is manifested by G2/M arrest, decreased DNA synthesis and increased apoptosis and is dependent upon the Ub ligase activity of the RING domain. Tumor formation in a nude mouse model is inhibited by TRC8 in a RING-dependent manner. Expression of TRC8 represses genes involved in cholesterol and fatty acid biosynthesis that are transcriptionally regulated by the sterol response element binding proteins (SREBPs). Expression of activated SREBP-1a partially restores the growth of TRC8-inhibited cells. These data suggest that TRC8 modulation of SREBP activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway.

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External Sources

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  2. DOI: 10.1038/sj.onc.1210017
  3. View record in Web of Science®
  4. WOS: 000245466000002

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