Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro1,2,3, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer4,5. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription6,7,8,9,10. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.
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We thank T. Maeda and T. Jacks for helpful suggestions; D. Peeper, C. Schmitt and M. Serrano for exchanging unpublished data and coordinating the submission of manuscripts; N. Hay, U. Greber and S. Hemmi for reagents; L. Cai and L. DiSantis for critical reading and editing of the manuscript; other members of the Pandolfi lab for advice and discussion; K. Manova and C. Farrell from the Molecular Cytology Core Facility for assistance with IHC analysis; and C. Le, C. Matei, D. Procissi and I. Buchanan for MRI analysis. This work was supported by NIH grants to P.P.P.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This file contains the experimental methods mentioned in the text, but data obtained are presented as the supplementary figures. The methods detailed include adenovirus for the infection of MEFs with Adenovirus expressing Cre, and autopsy and histopathology for the standard procedures of slide preparation from paraffin-embedded tissues. (DOC 32 kb)
This file contains figure legends for Supplementary Figure S1-S6 and Supplementary Table S1. This text will help readers to understand the experimental procedures and the conclusions in the text. (DOC 40 kb)
Scheme of Pten and Trp53 conditional knockout alleles. (PDF 70 kb)
Specificity of recombination. (PDF 5004 kb)
In vitro modelling of acute loss of Pten in MEFs. (PDF 1181 kb)
In vivo status of proliferation and signalling markers in the prostates of the indicated mutants and wt mice. (PDF 5017 kb)
In vitro senescence analysis. (PDF 4291 kb)
a, AP lobes of indicated genotypes reveal necessity for complete Pten loss for induction of senescence as measured by β-gal activity. Bars, 50µm. b, low magnifications of AP stained for β-gal activity from wt, Pten null and Pten-Trp53 double null mice. Bar, 10µm. (PDF 3920 kb)
Cryosections prepared from twelve different human radical prostatectomy specimens (collected under IRB approval) were analyzed for senescence with β-gal staining. (PDF 26 kb)
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Chen, Z., Trotman, L., Shaffer, D. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). https://doi.org/10.1038/nature03918
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