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

• Published in: Oncogene Vol. 26; no. 16; pp. 2263 - 2271
• Main Authors: BRAUWEILER, A, LORICK, K. L, LEE, J. P, TSAI, Y. C, CHAN, D, WEISSMAN, A. M, DRABKIN, H. A, GEMMILL, R. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05.04.2007; Nature Publishing Group
• Subjects: Amino Acid Sequence; Apoptosis; Biological and medical sciences; Cancer cells; Carcinoma; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Care and treatment; Cell Cycle; Cell Division; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cholesterol; Cholesterol - biosynthesis; Cloning, Molecular; DNA biosynthesis; Fundamental and applied biological sciences. Psychology; G2 Phase; Gene expression; Genetic aspects; Genetic disorders; Health aspects; Homeostasis; Humans; Hypoxia-inducible factors; Inhibitor drugs; Kidney - cytology; Kidney - physiology; Kidney cancer; Kidney diseases; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Nephrology. Urinary tract diseases; Oncology; Physiological aspects; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Renal cell carcinoma; Rodents; Sterol regulatory element-binding protein; Sterols; Transcription; Tumor suppressor genes; Tumors; Tumors of the urinary system; Ubiquitin; Ubiquitin-protein ligase; VHL protein; United States; Kidney disease; ubiquitin ligase; Urinary system disease; SREBP; Carbon-nitrogen ligases; Enzyme; Suppression; Malignant tumor; Hereditary; Carcinogenesis; clear-cell renal carcinoma; Clear cell carcinoma; Gene; Ligases; Kidney cancer; Grawitz tumor; RING-H2; Ubiquitin-protein ligase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210017

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-alpha. 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.