Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Chen, Z., Trotman, L. C., Shaffer, D., Lin, H. K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., Cordon-Cardo, C., Pandolfi, P. P. (August 2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature, 436 (7051). pp. 725-30. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/16079851
DOI: 10.1038/nature03918

Abstract

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro, 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 cancer. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. 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.

Item Type: Paper
Uncontrolled Keywords: ADP-Ribosylation Factors/metabolism Animals Cell Aging Cell Transformation, Neoplastic/genetics/ metabolism/pathology Cells, Cultured Female Fibroblasts Male Mice PTEN Phosphohydrolase Phenotype Phosphoric Monoester Hydrolases/ deficiency/genetics/metabolism Prostatic Neoplasms/genetics/ metabolism/ pathology Survival Analysis Tumor Suppressor Protein p53/deficiency/genetics/ metabolism Tumor Suppressor Proteins/ deficiency/genetics/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:
Communities: CSHL labs > Trotman lab
Depositing User: Matt Covey
Date: 4 August 2005
Date Deposited: 12 Mar 2013 14:09
Last Modified: 12 Mar 2013 14:09
PMCID: PMC1939938
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27770

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