p53: at the crossroad between cancer and ageing

Abstract

The p53 tumour suppressor plays an undisputed role in cancer. p53's tumour suppressive activity stems from its ability to respond to a variety of stresses to trigger cell cycle arrest, apoptosis or senescence, thereby protecting against malignant transformation. An increasing body of evidence suggests that p53 also drives organismal ageing. Although genetic models with altered p53 function display age-related phenotypes and thus provide in vivo evidence that p53 contributes to the ageing process, p53's role in organismal ageing remains controversial. Anti-cancer therapies that target p53 and reactivate or enhance its activity are considered good alternatives for treating various neoplasms. Therefore, it is important to determine whether these clinical approaches compromise tissue homeostasis and contribute to ageing. This review presents a number of models with altered p53 function and discusses how these models implicate p53 as part of a molecular network that integrates tumour suppression and ageing.

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

“…P53 is a major regulator of cellular senescence (reviewed in Papazoglu and Mills, 2007;Rodier et al, 2007;and Zuckerman et al, 2009). As E6AP has been shown to act as a regulator of p53 in HPV-infected cells (for review see Huibregtse et al, 1991;Scheffner et al, 1990Scheffner et al, , 1993Longworth and Laimins, 2004;andBeaudenon and Huibregtse, 2008) and in certain cells, such as prostate MEFs (p6).…”

How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?

“…Senescence and apoptosis are also processes likely to underlie central aspects of aging, so, unsurprisingly, increased attention has been paid to the role of p53 in regulating aging and longevity (Serrano and Blasco, 2007;Sharpless and DePinho, 2007) (Bauer and Helfand, 2006;Donehower and Levine, 2008;Gatza et al, 2005;Papazoglu and Mills, 2007). Table 1 summarizes some representative mouse models that exhibit alterations in longevity in which altered p53 levels and/or activity have been implicated.…”

Anti-tumor effects and cellular mechanisms of resveratrol

“…Resveratrol inhibited cell viability and clonogenic potential, as well as arrested cell cycle in the G1 phase and led to senescence instead of apoptosis. The underlying mechanisms of this effect is the deregulation of the cell cycle and senescence pathway molecularly, including cyclin D1, CDK4 and 6, p21 and p16, since p21 and p16 signaling pathways could participate in senescence progression mediated by various kinds of stress as demonstrated by previous studies (49,50). Treatment with resveratrol on the esophageal squamous cell carcinoma cell line (52) resulted in increase of autophagic response, marked by significant elevation of LC3-II in autophagosomes, up-regulation of multiple key autophagosomeregulatory proteins, such as Beclin-1 and ATG5, and the formation of acidic vesicular organelles (AVO), which was consistent with the cell death effect of resveratrol.…”