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Updated: Oct 1, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway
Robert M Gemmill1, Lynne T Bemis, Jason P Lee
1Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, Colorado, CO 80262, USA. robert.gemmill@uchsc.edu
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.
Insights
The VHL tumor suppressor gene and TRC8 protein interact and are functionally linked, suggesting a role in kidney cancer development. This discovery may lead to new therapeutic targets for renal carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Von Hippel-Lindau (VHL) protein is a key component of an SCF ubiquitin ligase complex involved in renal carcinoma.
- No mutations in VHL-interacting proteins have been found in wild-type VHL tumors.
- TRC8 gene translocations were previously identified in a family with hereditary renal and thyroid cancer.
Purpose of the Study:
- To investigate the functional relationship between VHL and TRC8.
- To explore the role of TRC8 in cellular processes and its potential link to kidney cancer.
Main Methods:
- Isolated and studied the Drosophila homologue of TRC8 (DTrc8).
- Utilized genetic manipulations and yeast two-hybrid screens in Drosophila.
- Performed GST-pulldown and co-immunoprecipitation experiments to confirm protein interactions.
- Investigated the localization of human and Drosophila TRC8 and JAB1 proteins.
Main Results:
- DTrc8 and DVHL exhibit identical ventral midline defects when lost, indicating functional linkage.
- Direct physical interactions were confirmed between DTrc8 and DVHL, and between DTrc8 and CSN-5/JAB1.
- Human JAB1 localization was found to be dependent on VHL mutant status.
- Overexpression of DTrc8 inhibited cell growth, supporting its role as a tumor suppressor.
Conclusions:
- VHL, TRC8, and JAB1 are physically and functionally interconnected.
- These three proteins likely play a role in the pathogenesis of kidney cancer.
- The findings suggest potential new avenues for understanding and treating renal carcinoma.
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