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Functions of TAp63 and p53 in restraining the development of metastatic cancer

Oncogene volume 33, pages 3325–3333 (2014)Cite this article

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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.

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Abbreviations

DMEM:

Dulbecco modified eagles medium

FBS:

fetal bovine serum

HGF:

hepatocyte growth factor

PDAC:

pancreatic ductal adenocarcinoma

RCP:

Rab coupling protein

WT:

wild type

TAp63:

transactivating domain-containing p63

ΔN:

amino-deleted p63

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Acknowledgements

Work in the labs of KHV and OJS was funded by CRUK. Work by PAJM and KHV was sponsored by the AICR. Part of the work was funded by AIRC (#5471) (2011-IG11955), AIRC 5xmille (#9979), Telethon Grant GGPO9133, Min. Salute (RF) to GM. We thank Dr N Rath and Dr M Olsen for providing the cDNA of mouse keratinocytes and Dr M Dobbelstein for providing the p63 promoter luciferase construct.

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Author notes

  1. P A J Muller

    Present address: 8Current address: MRC toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.,

  2. E H Tan and J P Morton: These authors contributed equally to the work.

Authors and Affiliations

  1. Cancer Research UK Beatson Institute, Glasgow, UK

    E H Tan, J P Morton, P Timpson, O J Sansom, K H Vousden & P A J Muller

  2. The Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Cancer Program, Sydney, Australia

    P Timpson

  3. Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK

    P Tucci & G Melino

  4. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy

    P Tucci

  5. Biochemistry Laboratory, Istituto Dermopatico dell′Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico and University of Rome ,“Tor Vergata,”, Rome, Italy

    G Melino

  6. Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

    E R Flores

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Correspondence to K H Vousden or P A J Muller.

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Tan, E., Morton, J., Timpson, P. et al. Functions of TAp63 and p53 in restraining the development of metastatic cancer. Oncogene 33, 3325–3333 (2014). https://doi.org/10.1038/onc.2013.287

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