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Title: Identification and functional analysis of a novel renal cell carcinoma (RCC) susceptibility gene from an RCC associated constitutional chromosomal translocation
Author: Wake, Naomi Catherine
ISNI:       0000 0004 2730 7117
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2013
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Familial renal cell carcinoma (RCC) only accounts for 3% of all RCC, yet the study of these inherited forms has provided important insights into the more common sporadic RCC. Somatic VHL inactivation is found in 70% of sporadic clear cell RCC (ccRCC) though is rarely found in other forms of RCC including papillary and chromophobe types. VHL-independent RCC tumourigenesis is poorly understood and current research involves identifying novel RCC candidate genes to further understand the mechanisms involved. In this study a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC was characterised using an oligonuleotide CGH array followed by genomic sequencing and the previously uncharacterised gene, UBE2QL1, was found to be disrupted by the 5p15.3 breakpoint. UBE2QL1 expression was down-regulated in 78.6% of sporadic RCC and UBE2QL1 promoter region hypermethylation and gene deletions were detected in 20.3% and 17.3% of sporadic RCC, respectively. Re-expression of UBE2QL1 in deficient RCC cell lines suppressed anchorage independent growth and colony formation. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and was shown to possess an active-site cysteine (C88) that is monoubiquitinated in vivo. In addition, UBE2QL1 co-immunoprecipitation and co-localisation studies demonstrated a protein interaction with FBXW7 (an F box protein for the SCF E3 ubiquitin ligase) and was shown to facilitate the degradation of the known FBXW7 substrates, cyclin E1 and mTOR. These findings demonstrate that UBE2QL1 functions as a novel renal tumour suppressor gene and ubiquitin conjugating enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; RC Internal medicine