No conflicts of interest were declared.
p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma†
Article first published online: 17 JUN 2010
Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 222, Issue 2, pages 129–137, October 2010
How to Cite
Doyle, B., Morton, J. P., Delaney, D. W., Ridgway, R. A., Wilkins, J. A. and Sansom, O. J. (2010), p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. J. Pathol., 222: 129–137. doi: 10.1002/path.2748
- Issue published online: 1 SEP 2010
- Article first published online: 17 JUN 2010
- Manuscript Accepted: 10 JUN 2010
- Manuscript Revised: 26 MAY 2010
- Manuscript Received: 15 MAR 2010
- Cancer Research UK
- Re-use of this article is permitted in accordance with the Terms and Conditions set out at . [http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms]
- pleomorphic rhabdomyosarcoma;
- transgenic mouse model
Pleomorphic rhabdomyosarcoma is the most common variant of this tumour in adults and has a very poor outcome. Two genes which are known to play a role in rhabdomyosarcoma development are KRas and p53. In the majority of human tumours, p53 abnormalities are point mutations that result in the expression of a mutant form of the protein. It is now hypothesized that these mutant forms of p53 may be playing an oncogenic role, over and above simple loss of the wild-type function. In this study, we use Cre-LoxP technology to develop a novel mouse model of rhabdomyosarcoma, crossing mice expressing a common KRas mutation (G12V) with mice that either lose p53 expression or express a mutant form of p53. We use this model to explore the different effects of p53 loss and mutation in the setting of an activating KRas mutation. We found that either complete loss of p53 (p53) or the expression of one mutant p53 allele with concomitant loss of the second allele (p53) resulted in the rapid development of rhabdomyosarcoma in 15/16 and 19/19 mice, respectively. In contrast, there was a marked difference between mice which lose a single copy of p53 (p53) and mice expressing a single copy of mutant p53 (p53). Fourteen out of 16 p53 mice developed rhabdomyosarcoma, compared with two out of 31 p53 mice. As a consequence of this, p53 mice had a median lifespan nearly double that of the p53 mice. To underline the enhanced effect of p53 mutation in tumour progression, metastases were seen only in those mice which expressed the mutant form. These data demonstrate that mutant p53 can co-operate with activated, mutant KRas to influence tumourigenesis and metastatic potential, over and above simple loss of normal protein function. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.