UBE 2 QL 1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Naomi C Wake,Andrew S Turnell,Michael Brown,Christopher J Ricketts,Anne‐Bine Skytte,Shirley Hodgson,Susan M Gribble,Elena Prigmore,Emma R Woodward,Noel Clarke,Mark R Morris,Rosamonde E Banks,Eamonn R Maher

doi:10.1002/humu.22433

Abstract

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gene.

Highlights

Renal cell carcinoma (RCC) is the most common adult renal tumor and is genetically and histologically heterogeneous [Kovacs et al, 1997; Maher, 2011]
UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR
We identified an uncharacterized gene, UBE2QL1, that was disrupted by a t(5;19)(p15.3;q12) associated with a familial predisposition to renal cell carcinoma (RCC), and demonstrated that UBE2QL1 has tumor suppressor activity and is inactivated in a subset of sporadic RCC by promoter region hypermethylation and/or deletions

Summary

Introduction

Renal cell carcinoma (RCC) is the most common adult renal tumor and is genetically and histologically heterogeneous [Kovacs et al, 1997; Maher, 2011]. Germline mutations in the VHL (MIM #608537) tumor suppressor gene (TSG) cause the familial cancer syndrome von Hippel–Lindau disease (MIM #193300) and somatic VHL inactivation is found in at least 80% of sporadic clear cell RCC [Banks et al, 2006; Foster et al, 1994; Gnarra et al, 1994; Latif et al, 1993; Maher et al, 1991]. 13 RCC-associated translocations have been described and, in some cases, characterization of the breakpoints has led to the identification of candidate TSGs (e.g., FHIT, LSAMP, NORE1) that have been implicated in sporadic renal tumorigenesis [Cohen et al, 1979; Kuiper et al, 2009; Woodward et al, 2010]. The association of constitutional chromosome 3 translocations with RCC has been well established [Woodward et al, 2010], the significance of

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