The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway
- 16 May 2002
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 21 (22), 3507-3516
- https://doi.org/10.1038/sj.onc.1205437
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.Keywords
This publication has 48 references indexed in Scilit:
- The pVHL-associated SCF ubiquitin ligase complex: Molecular genetic analysis of elongin B and C, Rbx1 and HIF-1α in renal cell carcinomaOncogene, 2001
- Membrane Topology and Function of Der3/Hrd1p as a Ubiquitin-Protein Ligase (E3) Involved in Endoplasmic Reticulum DegradationPublished by Elsevier BV ,2001
- The von Hippel–Lindau tumor suppressor proteinCurrent Opinion in Genetics & Development, 2001
- PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells is mediated by p27kip1Oncogene, 2000
- p38 Binds to the Intracellular Precursor of the Lutropin/Choriogonadotropin Receptor and Promotes Its DegradationPublished by Elsevier BV ,2000
- Biochemical evidence that Patched is the Hedgehog receptorNature, 1996
- The Drosophila melanogaster similar bHLH-PAS gene encodes a protein related to human hypoxia-inducible factor 1α and Drosophila single-mindedGene, 1996
- Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma SyndromeCell, 1996
- Note on the integrability of superharmonic functionsProceedings of the American Mathematical Society, 1993
- Hereditary Renal-Cell Carcinoma Associated with a Chromosomal TranslocationNew England Journal of Medicine, 1979