title: Functions of TAp63 and p53 in restraining the development of metastatic cancer.
abstract: Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous depletion of both p53 and TAp63 can recapitulate the effect of mutant p53 expression in vivo, we used a mouse model of pancreatic cancer in which the expression of mutant p53 resulted in the rapid appearance of primary tumours and metastases. As shown previously, loss of one allele of wild-type (WT) p53 accelerated tumour development. A change of one WT p53 allele into mutant p53 did not further accelerate tumour development, but did promote the formation of metastasis. By contrast, loss of TAp63 did not significantly accelerate tumour development or metastasis. However, simultaneous depletion of p53 and TAp63 led to both rapid tumour development and metastatic potential, although the incidence of metastases remained lower than that seen in mutant p53-expressing tumours. TAp63/p53-null cells derived from these mice also showed an enhanced ability to scatter and invade in tissue culture as was observed in mutant p53 cells. These data suggest that depletion of TAp63 in a p53-null tumour can promote metastasis and recapitulate-to some extent-the consequences of mutant p53 expression.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: E H
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: 1] Cancer Research UK Beatson Institute, Glasgow, UK [2] The Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Cancer Program, Sydney, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Timpson
authors.affiliation: 1] Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK [2] Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tucci
authors.affiliation: 1] Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK [2] Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico and University of Rome ,"Tor Vergata," Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Flores
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: O J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: K H
authors.initials: KH
authors.lastname: Vousden
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: P A J
authors.initials: PA
authors.lastname: Muller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins