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Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

A Corrigendum to this article was published on 26 May 2011

Abstract

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence1,2. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies3. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma4,5. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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Figure 1: Reactivation of p53 results in liver tumour regression.
Figure 2: The primary response to p53 reactivation is not apoptosis.
Figure 3: p53 reactivation induces cellular senescence.
Figure 4: Clearance of liver tumours by an innate immune response.

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Acknowledgements

We thank L. Bianco and M. Jiao for technical assistance. We also thank G. Evan, T. Jacks, A. Ventura, M. Narita, A. Chicas, M. Yon, G. Hannon and other members of the Lowe and Hannon laboratories for advice and discussions. We thank M. McCurrach for editorial assistance. W.X. is in the MCB graduate program at Stony Brook University. This work was generously supported by the Emmy Noether Programme of the German Research Foundation, Alan and Edith Seligson, the Don Monti Foundation, and grants from the National Institutes of Health (C.C.C, S.W.L.). This work is dedicated to our friend and colleague Dr. Enrique (Henry) Cepero.

Author Contributions W.X.: study design and conduction of experiments; L.Z.: study design and conduction of experiments; C.M.: design and conduction of flow cytometry experiments; R.A.D.: vector development; E.H.: histopathological analyses; V.K.: microarray analysis; C.C.C: histopathological analyses; S.W.L.: study design, principal investigator.

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Correspondence to Scott W. Lowe.

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Xue, W., Zender, L., Miething, C. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). https://doi.org/10.1038/nature05529

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