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RING-Dependent Tumor Suppression and G2/M Arrest Induced by the TRC8 Hereditary Kidney Cancer Gene

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RING-Dependent Tumor Suppression and G2/M Arrest Induced by the TRC8 Hereditary Kidney Cancer Gene Oncogene (2007) 26, 2263–2271 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene A Brauweiler1, KL Lorick2, JP Lee1, YC Tsai2, D Chan1, AM Weissman2, HA Drabkin1 and RM Gemmill1 1Division of Medical Oncology, Department of Medicine, University of Colorado at Denver and Health Sciences Center and University of Colorado Cancer Center, Aurora, CO, USA and 2Lab of Protein Dynamics and Signaling, National Cancer Institute, Fort Detrick, Frederick, MD, USA TRC8/RNF139 and von Hippel–Lindau (VHL) both membrane-associatedE3 ubiquitin (Ub) ligase disrupted encode E3 ubiquitin (Ub) ligases mutated in clear-cell by the translocation (Gemmill et al., 2002). The renal carcinomas (ccRCC). VHL, inactivated in nearly targeting subunit of a secondE3 ligase, encodedby 70% of ccRCCs, is a tumor suppressor encoding the the von Hippel–Lindau gene (VHL), is defective in most targeting subunit for a Ub ligase complex that down- sporadic clear-cell renal cell carcinomas (ccRCC) regulates hypoxia-inducible factor-a. TRC8/RNF139 is a (Kaelin, 2005). The best-known targets for the VHL putative tumor suppressor containing a sterol-sensing E3 ligase are the hypoxia-inducible transcription (HIF) domain and a RING-H2 motif essential for Ub ligase factors, HIF-1 and-2 a . The HIF system represents a activity. Here we report that human kidney cells are major pathway for sensing oxygen levels andis directly growth inhibited by TRC8. Inhibition is manifested by linkedto kidney tumorigenesis. G2/M arrest, decreased DNA synthesis and increased A novel oxygen-sensing mechanism involving lipid apoptosis and is dependent upon the Ub ligase activity of homeostasis was recently described in fission yeast the RING domain. Tumor formation in a nude mouse (Hughes et al., 2005; Todd et al., 2006). The sterol model is inhibited by TRC8 in a RING-dependent manner. regulatory element binding protein (SREBP) homolog Expression of TRC8 represses genes involved in choles- in Schizosaccharomyces pombe, Sre1, is activatedby terol and fatty acid biosynthesis that are transcriptionally oxygen limitation while mutations in Sre1 inhibit cell regulated by the sterol response element binding proteins growth under severe hypoxia (Hughes et al., 2005). In (SREBPs). Expression of activated SREBP-1a partially mammalian cells, the SREBP transcription factors are restores the growth of TRC8-inhibited cells. These data responsible for coordinately inducing cholesterol and suggest that TRC8 modulation of SREBP activity fatty acidbiosynthetic enzymes, such as 3-hydroxy-3- comprises a novel regulatory linkbetween growth control methylglutaryl coenzyme A reductase (HMGCR) (Hor- and the cholesterol/lipid homeostasis pathway. ton et al., 2003; Goldstein et al., 2006). Interestingly, Oncogene (2007) 26, 2263–2271. doi:10.1038/sj.onc.1210017; ccRCCs contain abundant lipid inclusions composed of publishedonline 2 October 2006 newly synthesizedcholesterol esters andother neutral lipids (Clayman et al., 1986; Gebhard et al., 1987), Keywords: ubiquitin ligase; SREBP; clear-cell renal suggesting that deregulation of lipid homeostasis is carcinoma; RING-H2 characteristic for these tumors. OverexpressedSREBPs have been foundin a variety of tumor types, including prostate (Ettinger et al., 2004), breast (Martel et al., 2006) andglioblastoma (Ma et al., 2005), andwe have identified similar changes in ccRCCs (Lee et al., Introduction submitted). Only 60–70% of ccRCCs have direct defects in the The TRC8/RNF139 gene was identified in a unique VHL pathway andsearches for mutations in other family with the constitutional translocation, components of the VHL complex have proven negative t(3;8)(3p14.2;q24.1), andhereditary renal andthyroid (Clifford et al., 2001). VHL loss alone appears cancer (Cohen et al., 1979; Li et al., 1993; Gemmill et al., insufficient for tumor development, suggesting that 1998). TRC8 encodes an endoplasmic reticulum (ER) alterations in additional genes and/or regulatory path- ways are necessary (Mandriota et al., 2002). One Correspondence: Professor RM Gemmill, Division of Medical candidate is TRC8 (Gemmill et al., 1998, 2002, 2005), Oncology, University of Colorado at Denver and Health Sciences a 60 kDa ER protein with 10 predicted transmembrane Center andUniversity of ColoradoCancer Center, 12801 E. 17th segments anda sterol-sensing domain(Gemmill et al., Avenue, Mail Stop 8117, PO Box 6511, Aurora 80045-0511, CO, USA. E-mail: [email protected] 1998), similar to those foundin SCAP andHMGCR Received19 June 2006; revised16 August 2006; accepted18 August 2006; that confer sterol-sensitivity to the SREBP/lipidhomeo- publishedonline 2 October 2006 static pathway (Goldstein et al., 2006). We have recently RING-dependent tumor suppression by TRC8 A Brauweiler et al 2264 discovered that TRC8 stability is sterol-regulated (Lee ectopic TRC8 expression (Figure 1a). Co-expression of et al., submitted). TRC8 also contains a RING-H2 enhancedgreen fluorescent protein (EGFP) indicated domain in the C-terminus that catalyses in vitro transfection efficiency. Ad-TRC8 infection (multiplicity ubiquitylation reactions (Lorick et al., 1999). In of infection (MOI) of 50, >90% EGFP positive) Drosophila, DTrc8 is a potent growth suppressor and resultedin a five-foldreductionin cell proliferation appears to function in conjunction with, or parallel to, after 48 h comparedto cells infectedwith Ad-EGFP DVhl (Gemmill et al., 2002). Here we demonstrate that alone (Figure 1b). Flow cytometry (SKRC-09 is shown TRC8 is a potent growth suppressor in mammalian in Figure 1c) revealeda large increase in the sub-G1 cells, inducing G2/M arrest, decreased DNA synthesis apoptotic fraction in Ad-TRC8-infected cells compared andincreasedapoptosis. These in vitro effects, along to controls (Figure 1d). These results support a tumor- with in vivo inhibition of tumorigenicity, are dependent suppressive function for TRC8 through inhibition of cell upon the Ub ligase activity of the RING domain. TRC8 proliferation and induction of cell death. inhibits the expression of SREBP-regulatedgenes and To investigate these effects further, we utilizedhuman ectopic expression of activatednuclear SREBP embryonic kidney (HEK293) FlpIn TRex cells (293FI) (nSREBP) partially restores growth to TRC8-inhibited in which TRC8 was placedunder the control of a cells. Our results suggest that TRC8 is a tumor tetracycline-inducible promoter (Figure 2a). Consistent suppressor implicatedin a novel regulatory relationship with the adenovirus results, TRC8 suppressed the linking the cholesterol/lipidbiosynthetic pathway with proliferation of 293FI cells comparedto doxycycline cellular growth control. (dox)-treated control cells (Figure 2b). Flow cytometry demonstrated that TRC8 induced apoptosis and in- creasedcell populations with 4 N DNA content, consistent with G2/M arrest (Figure 2c). Bromodeox- Results yuridine (BrdU) incorporation, indicative of DNA synthesis, was suppressedby TRC8 (Figure 2d).These TRC8 inhibits proliferation of transformed kidney cells data indicate that in 293FI cells, TRC8 blocks Adenovirus infection of three ccRCC cell lines (SKRC- proliferation by inhibiting DNA synthesis, increasing 02, -09 and-17) was usedto assess short-term effects of apoptosis andinducingcell-cycle arrest. Figure 1 TRC8 inhibits growth of RCC cell lines in vitro.(a) Adenoviral constructs expressing EGFP alone (EGFP) or EGFP with TRC8 were introduced into three ccRCC cell lines (SKRC-02, -09 and -17) using an MOI of 50. Microscopic examination 24 h post- infection confirmed>90% expressedEGFP (not shown). Lysates (48 h) were analysedby Western blot for TRC8 expression using anti-HA antibody Y-11. Tubulin provided a loading control. (b) Cells were platedin triplicate andinfectedwith control or TRC8- encoding adenoviruses (MOI ¼ 50). After 48 h, total viable cells were countedusing trypan-blue exclusion. Cell numbers were normalizedto the EGFP controls. ( c and d) Parallel cultures were analysedby flow cytometry 48 h post-infection. ( c) Cell cycle profile of TRC8-Ad-infected SKRC-09 cells compared to EGFP-Ad-infected controls. (d) Quantitation of apoptotic sub-G1 population (percent of total). Oncogene RING-dependent tumor suppression by TRC8 A Brauweiler et al 2265 et al., 2003). PurifiedGST fusion proteins (Figure 3c) were assayedin reactions containing 32P-labelledUb, E1, ATP andUbe2d2(formerly UbcH5b). Reaction products were analysed by sodium dodecyl sulfate– polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography (Figure 3b). Wild-type GST-TRC8 generatedprominent ubiquitylation productscontaining Ub multimers up to 3 andsmall amounts of higher molecular weight adducts (lane 2). The positive control GST-AO7 (lane 7), a RING domain-containing protein with well-defined Ub ligase activity, yielded abundant higher molecular weight products (Lorick et al., 1999). In contrast, mutation of the Zn2 þ -coordinating Cys residues in the CAIC and CPMC mutations resulted in nearly total ablation of ubiquitylation activity (lanes 3 and 6). Thus, as expected, direct disruption of the Zn2 þ coordinating sites eliminated ubiquitylation activity for the TRC8 RING domain. The remaining mutations affected amino acids outside the Zn2 þ binding sites and showeddifferential effects on ubiquitylation. LRK (lane 5) lost all activity while SAR (lane 4) retained about 30% of wild-type activity. Growth suppression mediated
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