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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.

Type Journal
ISBN 1476-5594 (Electronic) 0950-9232 (Linking)
Authors Tan, E. H.; Morton, J. P.; Timpson, P.; Tucci, P.; Melino, G.; Flores, E. R.; Sansom, O. J.; Vousden, K. H.; Muller, P. A.;
Garvan Authors Dr Paul Timpson
Publisher Name ONCOGENE
Published Date 2014-01-01 00:00:00
Published Volume 33
Published Issue 25
Published Pages 3325-33
URL http://www.ncbi.nlm.nih.gov/pubmed/23873029
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12452_12791/nihms568574.pdf