| | |  | | | | Record from Web of Science® | | | | | | |
| Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis |
|
|
| Author(s): Chen ZB, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP |
| Source: NATURE Volume: 436 Issue: 7051 Pages: 725-730 Published: AUG 4 2005 |
| Times Cited: 347 References: 30 |
| Abstract: Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro(1-3), 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 cancer(4,5). Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription(6-10). 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Pandolfi, PP (reprint author), Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA |
Addresses:
1. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA
2. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Pathol, New York, NY 10021 USA
3. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Med, New York, NY 10021 USA
4. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Radiol, New York, NY 10021 USA
5. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Med Phys, New York, NY 10021 USA
6. Columbia Univ, Inst Canc Genet, Dept Anat & Cell Biol, New York, NY 10032 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 951XA |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature03918 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |