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Restoration of p53 function leads to tumour regression in vivo

Abstract

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes1. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance2,3,4,5; this phenotype is referred to as oncogene addiction6. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR7,8,9,10. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers11, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.

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Figure 1: Generation of the p53-LSL allele.
Figure 2: p53 restoration leads to tumour regression in vivo.
Figure 3: p53 restoration in lymphomas leads to apoptosis.
Figure 4: p53 restoration in sarcomas leads to growth suppression with features of cellular senescence.

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Acknowledgements

We thank N. Willis for helping to generate the LSL mice, H. Zheng for imaging mice, G. Wojtkiewicz for generating the movies with three-dimensional reconstruction, D. Crowley for help with histology, R. Bronson for reviewing the pathology, and M. Hemann for suggestions. A.V. is grateful to D. Ventura and G. Terranova for continuous support and encouragement. This work was supported by the Howard Hughes Medical Institute (T.J.), NCI (T.J., R.W., D.G.K.), and partially by a Cancer Center Support grant from the NCI (M.I.T.), the American Italian Cancer Research Foundation (A.V.), and the Leaf fund (D.G.K.). T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. D.A.T. is a Rita Allen Foundation Scholar.

Author Contributions A.V., D.G.K. and T.J. designed the experiments and wrote the paper. D.T. generated the p53-LSL mice and M.E.M. generated and characterized the Cre-ERT2 mice, determined the optimal Tamoxifen dosage, assisted with histopathological analysis and commented on the manuscript. A.V., D.G.K. and L.L. derived and characterized the tumour cell lines. A.V. performed the immunostainings, the TUNEL assays the SA-β-Gal stainings and the western blottings. A.V., D.K. and L.L. performed the tamoxifen intraperitoneal injections. E.E.R. derived the MEFs. L.L. and J.N. maintained the mouse colony and genotyped the animals. J.G. and D.G.K. evaluated the magnetic resonance images, J.G. supervised the magnetic resonance imaging, generated the three-dimensional reconstructions and determined tumour volumes. R.W. optimized in vivo imaging protocols, reviewed imaging data, discussed the results, and commented on the manuscript.

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Supplementary information

Supplementary file 1

This file contains Supplementary Methods, Supplementary Figures 1, 3, 5, 6 and 7 with legends. The Supplementary Figures 2 and 4 are represented as movie files. (PDF 3041 kb)

Supplementary file 2

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 2. (AVI 6872 kb)

Supplementary file 3

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 2. (AVI 7219 kb)

Supplementary file 4

This file contains movies of MRIs indicated in the main text as Supplementary Figures. (MOV 169 kb)

Supplementary file 5

This file contains movies of MRIs indicated in the main text as Supplementary Figures 2. (MOV 185 kb)

Supplementary file 6

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Supplementary file 8

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 4. (AVI 6481 kb)

Supplementary file 9

This file contains movies of 3D reconstructions indicated in the main text as Supplementary Figures 4. (AVI 6200 kb)

Supplementary file 10

This file contains movies of MRIs indicated in the main text as Supplementary Figures 4. (MOV 243 kb)

Supplementary file 11

This file contains movies of MRIs indicated in the main text as Supplementary Figures 4. (MOV 341 kb)

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Ventura, A., Kirsch, D., McLaughlin, M. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007). https://doi.org/10.1038/nature05541

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