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)
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: |
https://repository.cshl.edu/id/eprint/27770 |
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