Abstract
Protein p21Cip1/Waf1 is transcriptionally activated by the tumour suppressor p53 and previous studies have shown that p21 plays a role in tumour suppression. However, the involvement of p21 in p53-mediated tumour suppression remains to be directly demonstrated in vivo. Tumour suppression mediated by p53 can be measured by comparing tumour susceptibility in animals carrying two (wild-type mice) or three (super-p53 mice) copies of the p53 gene. We have taken advantage of this genetically defined system to measure p53-mediated cell-cycle arrest, apoptosis and tumorigenesis, in a p21 wild-type and in a p21-null context. The absence of p21 significantly impaired the enhanced p53-mediated cell-cycle arrest characteristic of super-p53 cells, but did not affect the enhanced apoptosis. Importantly, in an experimental model of fibrosarcoma induction, the absence of p21 significantly decreased the tumour suppression benefit of super-p53 mice. We conclude that cell-cycle arrest through p21 plays a significant role in mediating p53-dependent cancer protection.
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Acknowledgements
We are indebted to Maribel Muñoz for excellent mouse colony management and animal care, and to Elisa Santos for mouse genotyping. AE is funded by a predoctoral fellowship from the Spanish Ministry of Education and Science (MEC). SV-M is funded by the Ramon y Cajal Program of the MEC. Work at the laboratory of MS has been funded by the CNIO, the MEC (SAF2005-03018) and by the European Union (INTACT, PROTEOMAGE).
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Efeyan, A., Collado, M., Velasco-Miguel, S. et al. Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression. Oncogene 26, 1645–1649 (2007). https://doi.org/10.1038/sj.onc.1209972
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DOI: https://doi.org/10.1038/sj.onc.1209972
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