title: UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene.
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.
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Wake
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morris
authors.forename: Elena
authors.initials: E
authors.lastname: Prigmore
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gribble
authors.forename: Anne-Bine
authors.initials: AB
authors.lastname: Skytte
authors.forename: Michael
authors.initials: M
authors.lastname: Brown
authors.forename: Noel
authors.initials: N
authors.lastname: Clarke
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.forename: Shirley
authors.initials: S
authors.lastname: Hodgson
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Turnell
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
mesh_terms: D000328:Adult; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D056905:Chromosome Breakpoints; D002888:Chromosomes, Human, Pair 19; D002895:Chromosomes, Human, Pair 5; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D014178:Translocation, Genetic; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C000588845:UBE2QL1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases
keywords: FBXW7; UBE2QL1; renal cell carcinoma; ubiquitin conjugating enzyme