UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene

Research output: Contribution to journalArticle

Authors

  • Naomi C. Wake
  • Elena Prigmore
  • Susan M. Gribble
  • Anne-bine Skytte
  • Michael Brown
  • Noel Clarke
  • Rosamonde E. Banks
  • Shirley Hodgson

External organisations

  • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus; Hinxton Cambridge UK
  • Department of Clinical Genetics; Vejle Hospital; Vejle Denmark
  • Genito Urinary Cancer Research Group; School of Cancer and Enabling Sciences, Paterson Institute for Cancer Research, The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust; Manchester UK
  • Cancer Research UK Clinical Centre; St. James's University Hospital; Leeds UK
  • South West Thames Regional Genetics Service; St. George's Medical School, University of London; London UK

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.

Details

Original languageEnglish
Pages (from-to)1650-1661
JournalHuman Mutation
Volume34
Issue number12
Early online date7 Oct 2013
Publication statusPublished - 1 Dec 2013

Keywords

  • renal cell carcinoma, UBE2QL1, ubiquitin conjugating enzyme, FBXW7