Delayed ageing through damage protection by the Arf/p53 pathway

Nature 448: 375-379, 2007

Speaker: 沈郁婷                     Date:2007/10/03 13:10~14:00
Commentator: 徐麗君 老師            Place: Room 601

Abstract:

The p53 protein is activated in a specific manner by post-translational modifications, and this leads to either cell cycle arrest, a program that induces cell senescence, or cell apoptosis. Among the p53-responsive gene products are p21CIP1, a potent inhibitor of cyclin-dependent kinases, and Mdm2, a negative feedback regulator that helps terminate the p53 response. By inhibiting Mdm2, ARF stabilizes and activates p53, braking the cell cycle in response to inappropriate mitogenic signals [1]. Cancer and ageing are both fuelled by the accumulation of cellular damage. In this study, the authors hypothesized that those mechanisms that protect cells from damage simultaneously provide protection against cancer and ageing. Among the mechanisms that prevent cellular damage are those improve the efficiency of energy consumption, therefore decreasing the generation of reactive oxygen species (ROS), which are considered to be a main source of endogenous damage [2].The authors have reasoned that Arf/p53, the tumor-suppressor pathway, could have anti-ageing activity by alleviating the load of age-associated damage. They compared s-ARF/p53 and s-p53 or s-Arf transgenic mice, and demonstrated that increasing the gene dosage of Ink4b-Arf-Ink4a and p53 results in a significant enhancement in cancer resistance and delay of ageing. Previous studies indicated that there are several possible mechanisms involved in ageing, including decreases in metabolism, IGF-1 levels, telomere shortening, and oxidative damage. They found that decreased generation of ROS in young and old ages of s-Arf/p53 mice. These observations extend the protective role of Arf/p53 in ageing against damage.

References:

1. Sandra L Harris et al (2005). The p53 pathway: positive and negative feedback loops. Oncogene 24: 2899-908.

2. Manuel Serrano et al (2007) Cancer and ageing: convergent and divergent mechanisms. Nature reviews molecular cell biology 8: 715-22