TAILIEUCHUNG - Báo cáo khoa học: Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model

TP53is one of the most commonly mutated genes in human tumours. Variations in the types and frequencies of mutations at different tumour sites suggest that they may provide clues to the identity of the causative mutagenic agent. A useful model for studying humanTP53mutagenesis is the partial human TP53knock-in (Hupki) mouse containing exons 4–9 of humanTP53in place of the corresponding mouse exons. | ỊFEBS Journal REVIEW ARTICLE Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in Hupki mouse model Jill E. Kucab David H. Phillips and Volker M. Arlt Section of Molecular Carcinogenesis Institute of Cancer Research Sutton Surrey UK Keywords cancer aetiology environmentalcarcinogen Hupki immortalization mutation assay TP53 Correspondence V. M. Arlt Section of Molecular Carcinogenesis Institute of Cancer Research Brookes Lawley Building Sutton Surrey SM2 5NG UK Fax 44 0 208 722 4052 Tel 44 0 208 722 4405 E-mail Invited review following the FEBS Anniversary Prize of the Gesellschaft fur Biochemie und Molekularbiologie received on 5 July 2009 at the 34th FEBS Congress in Prague Received 1 February 2010 revised 2 April 2010 accepted 8 April 2010 doi TP53 is one of the most commonly mutated genes in human tumours. Variations in the types and frequencies of mutations at different tumour sites suggest that they may provide clues to the identity of the causative mutagenic agent. A useful model for studying human TP53 mutagenesis is the partial human TP53 knock-in Hupki mouse containing exons 4-9 of human TP53 in place of the corresponding mouse exons. For an in vitro assay embryo fibroblasts from the Hupki mouse can be examined for the generation and selection of TP53 mutations because mouse cells can be immortalized by mutation of Tp53 alone. Thus far four environmental carcinogens have been examined using the Hupki embryo fibroblast immortalization assay a UV light which is linked to human skin cancer b benzo a pyrene which is associated with tobacco smoke-induced lung cancer c 3-nitrobenzanthrone a suspected human lung carcinogen linked to diesel exposure and d aristolochic acid which is linked to Balkan endemic nephropathy-associated urothelial cancer. In each case a unique TP53 mutation pattern was generated that corresponded to the pattern found in human .

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