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

• Published in: Oncogene Vol. 21; no. 22; pp. 3507 - 3516
• Main Authors: GEMMILL, Robert M, BEMIS, Lynne T, LEE, Jason P, SOZEN, M. Ali, BARON, Anna, ZENG, Chan, ERICKSON, Paul F, HOOPER, Joan E, DRABKIN, Harry A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 16.05.2002; Nature Publishing Group
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; Carcinoma, Renal Cell - genetics; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; COP9 Signalosome Complex; COS Cells; DNA-Binding Proteins - analysis; Drosophila; Drosophila - chemistry; Drosophila - embryology; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - physiology; Endoplasmic reticulum; Endoplasmic Reticulum - chemistry; Female; Fundamental and applied biological sciences. Psychology; Genes, Tumor Suppressor; Health sciences; Humans; Immunoprecipitation; Insects; Intracellular Signaling Peptides and Proteins; Kidney cancer; Kidney Neoplasms - genetics; Kidneys; Ligases - genetics; Ligases - physiology; Localization; Male; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation; Oncology; Peptide Hydrolases; Preventive medicine; Protein Structure, Tertiary; Proteins; Receptors, Cell Surface; Renal function; Signal Transduction; Sterols; Thyroid cancer; Transcription Factors - analysis; Tumor suppressor genes; Tumor Suppressor Proteins; Tumors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein; Wings, Animal - embryology; United States > US; Colorado; Kidney disease; Human; Urinary system disease; Insecta; Molecular interaction; Carcinogenesis; Kidney; Drosophilidae; Genetic disease; Arthropoda; Tumor; Mutation; Invertebrata; Localization; Drosophila melanogaster; Diptera; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205437

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.