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

Oncogene volume 26, pages 2263–2271 (2007)Cite this article

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 downregulates hypoxia-inducible factor-α. 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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Acknowledgements

We thank H Schulze for expression plasmids, A Kraft for vectors and 293FI cells. This investigation used the DNA Sequencing, Flow Cytometry and Biostatistics Cores of the University of Colorado Cancer Center. We thank J Jacobsen, C Korch, K Helm, M Ashton, C Childs and C Zeng for technical assistance. KLL, YCT and AMW are supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. HAD and RMG are supported by NIH RO1 CA076035.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Colorado at Denver and Health Sciences Center and University of Colorado Cancer Center, Aurora, CO, USA

    A Brauweiler, J P Lee, D Chan, H A Drabkin & R M Gemmill

  2. Lab of Protein Dynamics and Signaling, National Cancer Institute, Fort Detrick, Frederick, MD, USA

    K L Lorick, Y C Tsai & A M Weissman

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  1. A Brauweiler
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  2. K L Lorick
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  3. J P Lee
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  6. A M Weissman
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  7. H A Drabkin
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  8. R M Gemmill
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Correspondence to R M Gemmill.

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Supplementary Information accompanies the paper on the Oncology website (http://www.nature.com/ncponc).

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Brauweiler, A., Lorick, K., Lee, J. et al. RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene. Oncogene 26, 2263–2271 (2007). https://doi.org/10.1038/sj.onc.1210017

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