Increased Arf/p53 activity in stem cells, aging and cancer

Abstract

Arf/p53 pathway protects the cells against DNA damage induced by acute stress. This characteristic is the responsible for its tumor suppressor activity. Moreover, it regulates the chronic type of stress associated with aging. This is the basis of its anti-aging activity. Indeed, increased gene dosage of Arf/p53 displays elongated longevity and delayed aging. At a cellular level, it has been recently shown that increased dosage of Arf/p53 delays age-associated stem cell exhaustion and the subsequent decline in tissue homeostasis and regeneration. However, p53 can also promote aging if constitutively activated. In this context, p53 reduces tissue regeneration, which correlates with premature exhaustion of stem cells. We discuss here the current evidence linking the Arf/p53 pathway to the processes of aging and cancer through stem cell regulation.

Keywords: ARF; aging; p16; p53; stem cells.

Figure 1

Ink4/Rb‐ and Arf/p53‐mediated responses to cellular stress. In response to stress, cells activate Ink4/Rb and Arf/p53 signaling pathways in order to restore the homeostasis or eliminate themselves, preventing tumor formation in the case of acute oncogenic stress or alleviating accumulated cellular damage produced by chronic stress related to aging. p16^Ink4a blocks the cell cycle though its inhibitory action on the CDK/Cyclin D complexes, finally avoiding the E2F transcriptional action and the progression of cells from G1 to S phase. Arf promotes the degradation of the negative p53 regulator Mdm2, inducing p53 activation and, in consequence, p21‐mediated cell cycle arrest or senescence and/or PUMA‐mediated apoptosis.

Figure 2

Mouse models with regulated or deregulated Ink4/Rb and/or Arf/p53 pathways and their phenotypes with regard to tumor prevention and aging. Mutant mice with deregulated p53 hyperactivity display reduced tumor development but present premature aging and aging‐related diseases. Mice presenting a modest increase in normally regulated Ink4/Arf and p53 exhibit an enhanced tumor suppression capacity and normal aging. Mice presenting modest and regulated increases in both p53 and Ink4/Arf in the absence or presence of a constitutive telomerase reverse transcriptase (TERT) display resistance to tumor formation and present delayed aging. ‘m’ mice: Mice expressing a constitutively active truncated form of p53 lacking exons from 1 to 6 (Tyner et al., 2002); p44 tg mice: Mice presenting a constitutively active truncated form of p53 lacking exons from 1 to 3 (Maier et al., 2004), super p53 mice: Mice harboring an extra copy of the p53 intact gene (Garcia‐Cao et al., 2002); super Ink4a/Arf mice: mice with an extra intact Ink4/Arf locus (Matheu et al., 2004); MDM2 hypomorphic mice: mice with reduced Mdm2 levels (Mendrysa et al., 2006); ‘super Arf/p53’ mice: mice harboring an extra copy of p53 and Ink4/Arf (Matheu et al., 2007); ‘super Arf/p53/TERT’ mice: super Arf/p53 mice additionally presenting constitutive telomerase reverse transcriptase (TERT) (Tomas‐Loba et al., 2008).

Figure 3

Ink4/Rb and Arf/p53 pathways action on stem cell niches and aging modulation. Mice models with deregulated hyperactivation of p53 exhibit stem cell exhaustion along with tissue homeostasis disruption that promotes premature aging. However, mice with an extra copy of Ink4a/Arf/p53 display an improved maintenance of stem cells that provides tissue homeostasis delaying aging.