Two faces of p53: aging and tumor suppression

Francis Rodier, Judith Campisi, Dipa Bhaumik, Francis Rodier, Judith Campisi, Dipa Bhaumik

Abstract

The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells. In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation. However, both processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Moreover, whereas apoptotic cells are by definition eliminated from tissues, senescent cells can persist, acquire altered functions, and thus alter tissue microenvironments in ways that can promote both cancer and aging phenotypes. Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging. Here, we discuss the role of p53 as a key regulator of the DNA damage responses, and discuss how p53 integrates the outcome of the DNA damage response to optimally balance tumor suppression and longevity.

Figures

Figure 1.
Figure 1.
DNA damage response signaling pathways leading to p53 activation: DNA damage activates PIKK (ATM, ATR and DNA-PK), which leads to activation of checkpoint kinases (CHK1, CHK2) and p53. Activated p53 integrates the output of the DDR signaling network and triggers various cell fate decisions.
Figure 2.
Figure 2.
The impact of p53-mediated cell fate decisions on tissue homeostasis and organismal longevity: In the presence of severe DNA damage, effectors triggered by p53 cause transient cell growth arrest, apoptosis or senescence, which in turn promote tissue atrophy and organismal aging. In contrast, loss of p53 function prevents critical cell fate decisions and dramatically favors cancer.

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