Characterisation of a Novel Multi-Tissue Tumour Suppressor Gene in Mouse

O'Neill, Vincent John (2001) Characterisation of a Novel Multi-Tissue Tumour Suppressor Gene in Mouse. MD thesis, University of Glasgow.

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A considerable body of evidence from molecular, cytogenetic and functional studies points to the existence of a novel tumour suppressor gene on the long arm of human chromosome 7. This putative gene seems to be conserved between mouse and man, since a high frequency of allele loss is evident at mouse chromosome 6 band A2, the region syntenic to human chromosome 7q31, in the two-stage skin carcinogenesis system. In addition, introduction of human chromosome 7 into mouse tumour cell lines results in increased latency in tumorogenic assays, implying functional conservation. To date, this gene has not been isolated. I undertook loss of heterozygosity studies in a series of mouse skin tumours produced by the two-stage carcinogenesis protocol. After saturating the area of interest on mouse chromosome 6A2 with all available published microsatellite markers, I defined a possible smallest common deleted region between the markers D6mit83 and D6mit50. Allelotyping analysis of a panel of mouse cell lines representative of the sequential stages in skin carcinogenesis demonstrated allelic imbalance of markers on chromosome 6. FISH analysis of a selection of these cell lines using whole chromosome paints confirmed aneuploidy with tri- or tertrasomy of chromosome 6 being common. The finding of trisomy of chromosome 6 was seen in both papilloma and carcinoma cell lines, suggesting that this is an early event in skin carcinogenesis. Concurrent work in our laboratory on human chromosome 7 has generated a number of candidate tumour suppressor genes which map to chromosome 7q. Full-length cDNAs corresponding to three of these genes were cloned from a mouse foetal cDNA library, and analysed for mutational inactivation in the panel of mouse tumour cell lines. No mutations were evident. One of these genes was a novel homologue of kelch, an actin binding molecule first identified in Drosophila. This proved to possess both POZ and kelch repeat domains, commonly seen in the kelch family of genes, and showed a high degree of similarity to the human kelch homologue.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Genetics, Medicine
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-76027
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15

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