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The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

Oncogene volume 21, pages 3507–3516 (2002)Cite this article

Abstract

VHL is part of an SCF related E3-ubiquitin ligase complex with ‘gatekeeper’ function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.

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Acknowledgements

We thank W Kaelin for providing the 786-0 RCC cell line derivatives WT8 and PRC3, J West for sequence analyses and R Young for embryo injections. DNA samples were sequenced by the University of Colorado Cancer Center DNA Sequencing and Analysis Core Facility, supported by an NIH/NCI Cancer Core Support Grant (CA46934). This work was supported by a grant from the National Cancer Institute (CA76035) to HA Drabkin and RM Gemmill.

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Authors and Affiliations

  1. Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, 80262, Colorado, CO, USA

    Robert M Gemmill, Lynne T Bemis, Jason P Lee, M Ali Sozen, Paul F Erickson & Harry A Drabkin

  2. Department of Cellular and Structural Biology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, 80262, Colorado, CO, USA

    Joan E Hooper

  3. Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, 80262, Colorado, CO, USA

    Anna Baron & Chan Zeng

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  1. Robert M Gemmill
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Correspondence to Robert M Gemmill.

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Gemmill, R., Bemis, L., Lee, J. et al. The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Oncogene 21, 3507–3516 (2002). https://doi.org/10.1038/sj.onc.1205437

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