Senescence and aging: the critical roles of p53

Abstract

p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.

p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells

“…However, when TAp73 levels are coincidently decreased, PUMA transcription is blunted, and cells do not apoptose. Instead, as (i) levels of p21 waf-1 transcription are still high, and (ii) p53 has been shown to cause cell senescence via transcription of high levels of p21 waf-1 , 23 then cell senescence is the ultimate outcome. In this model, p53-dependent senescence is a 'fall-back' response that only occurs when cells are damaged and PUMA (and potentially other p53-dependent apoptotic genes) is not induced.…”

p53 Protein-mediated Up-regulation of MAP Kinase Phosphatase 3 (MKP-3) Contributes to the Establishment of the Cellular Senescent Phenotype through Dephosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2)

“…Currently, the mechanisms by which p53-targeted genes regulate senescence are still poorly understood. Most of them act on blockade of cell cycle progression and/or promotion of p53 activity (21). Linking p53 to ERK1/2 provides a novel mechanistic insight into the regulatory role of p53 on cellular senescence.…”

“…MKP-3 and ERK1/2 Are Downstream Targets of p53-Given that p53 plays a pivotal role in the establishment and maintenance of cellular senescence (21) and that p53 was characterized recently as a transcriptional factor of MKP-3 (22), we investigated the role of p53. Induction of cellular senescence with ETO was associated with an increased level of total and phosphorylated p53 (Fig.…”

Treatment with a Small Synthetic Compound, KMU-193, induces Apoptosis in A549 Human Lung Carcinoma Cells through p53 Up-Regulation

“…The tumor suppressor p53 has been implicated in many important cellular processes, including regulation of apoptotic cell death (Rufini et al, 2013). Evidence suggests crosstalk between p53 and caspases or other apoptosis regulatory proteins in induction of apoptosis in cancer cells (Amaral et al, 2010).…”