The p53 network: cellular and systemic DNA damage responses in aging and cancer

Abstract

Genome instability contributes to cancer development and accelerates age-related pathologies as evidenced by a variety of congenital cancer susceptibility and progeroid syndromes that are caused by defects in genome maintenance mechanisms. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis. Both senescence and apoptosis are powerful tumor-suppressive pathways preventing the uncontrolled proliferation of transformed cells. However, both pathways can potentially deplete stem and progenitor cell pools, thus promoting tissue degeneration and organ failure, which are both hallmarks of aging. p53 signaling is also involved in mediating non-cell-autonomous interactions with the innate immune system and in the systemic adjustments during the aging process. The network of p53 target genes thus functions as an important regulator of cancer prevention and aging.

Figure 1. p53 is activated downstream of the proximal DNA damage checkpoint signaling cascade in response to genotoxic damage or oncogene-induced replication stress.

The depicted checkpoint kinase complexes DNA-PK, ATM, ATR, CHK1, CHK2 and MK2 mediate DNA damage signaling, which funnels into activation of p53. Upon activation, p53 transcriptionally induces a host of target genes, which promote cell cycle arrest, allowing time for DNA repair, senescence or apoptosis leading to cell loss and ultimately contributing to tissue degeneration in aging. The fine balance between these different p53-mediated cellular outcomes translates into physiological consequences between cancer protection and aging. DSB, DNA double strand break; SSB, DNA single strand break.

Figure 2. Activation modes of p53 determine the physiological outcome.

(a) In wildtype cells and tissues, p53 exhibits low baseline activity through tight regulation of p53 protein levels. Only upon the appropriate cellular stress signals, such as those evoked by genotoxic lesions, p53 is activated to prevent oncogenic transformation of cells. (b) Increased tonic p53 activity, such as that induced by the expression of short p53 isoforms, promotes cancer resistance. However, the increased baseline activity of p53 appears to prevent tissue regeneration and to accelerate the aging process. (c) Low baseline levels with strong p53 activity only in response to appropriate stress stimuli, such as DNA damage, lead to extraordinary cancer protection with normal lifespan. Interestingly, recent data suggest that the physiological p53 response following exposure to ionizing radiation (IR) occurs in a non-linear oscillating fashion in repeating pulses with fixed amplitude and duration ^, . The observation of these oscillations became possible with recent advances in single-cell imaging techniques . This pulsatile behavior of p53 is induced by activation of p53 through ataxia telangectasia mutated (ATM) subsequently resulting in transactivation of Mouse double minute (Mdm)2 and Wild-type p53 induced phosphatase (Wip)1, two negative regulators of p53 . This induction of Mdm2 and Wip1 results in downregulation of p53 through a negative feedback loop. Such pulsatile waves of p53 activation occur in 4- to 7hr intervals at similar intensity until the DNA is fully repaired. In contrast to the IR response, UV irradiation causes a dose-dependent sustained induction of p53 that does not appear to result in oscillating waves . The role of IR-induced p53 pulses in determining cell fate remains to be elucidated.

Figure 3. Non-cell autonomous consequences of p53 signaling in aging (grey) and cancer (red) associated processes.

p53 induces several negative regulators of the cell intrinsic Insulin-like growth factor (IGF)-1 receptor signaling pathway as well as systemically acting IGF-BP3, the major antagonistic IGF-1 carrier in the circulation. IGF-1 signaling induces cell proliferation, while reduced IGF-1 signaling is associated with extended lifespan in species ranging from nematode worms to mammals. p53-mediated cellular senescence, in contrast, promotes cellular aging, while senescent cells modify their tissue environment through the senescence associated secretory phenotype (SASP) resulting in cytokine secretion that activates the innate immune system. The innate immune system in turn can act tumor suppressive (blue) by clearing cells that have become senescent as result of oncogene activation or chronic DNA damage. However, SASP might also have tumor promoting consequences on surrounding cells as cytokine signaling and chronic inflammation can promote proliferation of tumor cells. In addition, chronic inflammation is also associated with tissue aging.