Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis Journal Article
| Authors: | 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. |
| Article Title: | Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis |
| 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 nonlethal 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. |
| Keywords: | controlled study; survival analysis; gene mutation; nonhuman; animal cell; mouse; phenotype; animals; mice; gene; cells, cultured; cell cycle; protein stability; genetic transcription; oncology; protein p53; carcinogenesis; cell transformation, neoplastic; prostate cancer; prostatic neoplasms; tumor suppressor gene; prostate; tumors; tumor suppressor proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; fibroblasts; tumor suppressor protein p53; gene inactivation; malignant transformation; medicine; cell aging; phosphoric monoester hydrolases; mutagenesis; tryptophan; cells; mitosis inhibition; activation analysis; cellular senescence; trp53 gene; neoplastic transformation; noninvasive medical procedures; regulatory compliance; mutated genes; oncogenic pathways; adp-ribosylation factors |
| Journal Title: | Nature |
| Volume: | 436 |
| Issue: | 7051 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-08-04 |
| Start Page: | 725 |
| End Page: | 730 |
| Language: | English |
| DOI: | 10.1038/nature03918 |
| PUBMED: | 16079851 |
| PROVIDER: | scopus |
| PMCID: | PMC1939938 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 618" - "Export Date: 24 October 2012" - "CODEN: NATUA" - "Source: Scopus" |
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