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

Speaker: 林怜伶                        Date:10/12/2005 15:00-16:00

Commentator:劉校生老師                 Place: 601教室

Abstrate:

     Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, 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. In this study, the authors 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 vitroand in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, they detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Their 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.

References:

1.      Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

2.      Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307−315 (2004).