The cell death machinery governed by the p53 tumor suppressor in response to DNA damage

Abstract

The cellular response to genotoxic stress that damages DNA includes cell cycle arrest, activation of DNA repair, and in the event of irreparable damage, induction of apoptosis. However, the signals that determine cell fate, that is, survival or apoptosis, are largely unclear. The tumor suppressor p53 has been implicated in many important cellular processes, including regulation of apoptotic cell death. When cells encounter genotoxic stress, certain sensors for DNA lesions eventually stabilize and activate p53. Subsequently, p53 exerts its tumor suppressor function by transactivating numerous target genes. Active p53 is subjected to a complex and diverse array of covalent post-translational modifications, which selectively influence the expression of p53 target genes. In this regard, the molecular basis for how p53 induces apoptosis has been extensively studied; however, the relative contribution of each downstream effector is still to be explored. Moreover, little is known about precise mechanisms by which modified p53 is capable of apoptosis induction. A thorough understanding for the whole picture of p53 modification in apoptosis will be extremely valuable in the development of highly effective and specific therapies for cancer patients. This review is focused on the current views regarding the regulation of cell fate by p53 in the apoptotic response to DNA damage.

Figure 1

A hypothetical schema of a role for p53 on the critical checkpoint of cell fate in the apoptotic response to DNA damage. Following DNA damage, the cellular signaling is targeted to the nucleus, then the cell fate may be determined by p53 in the nucleus. The death signals are transmitted into the mitochondria or the receptors to induce apoptosis.

Figure 2

Functional domain and modification residues in p53. TAD indicates transactivation domain. NLS and NES mean nuclear localization and export signals, respectively. Modifications related to apoptosis are highlighted in red.

Figure 3

DNA damage‐induced transcriptional regulation of p53 gene by PKCδ and Btf or RREB‐1. Upon exposure to genotoxic stress, activated PKCδ induces Btf for co‐occupancy to CPE‐p53, thereby up‐regulating the expression of p53 at mRNA levels. p53 transcription is also induced by RREB‐1 via CPE‐p53 in response to DNA damage.

Figure 4

A proposed model for DYRK2‐mediated apoptosis in the cellular response to DNA damage. Upon exposure to genotoxic stress, p53 is stabilized and activated by phosphorylation at Ser15 and Ser20. Cytoplasmic DYRK2 is activated and targeted to the nucleus, and then phosphorylates p53 at Ser46. Ser46 phosphorylation of p53 triggers induction of apoptosis by up‐regulation of apoptosis‐related gene expression, such as p53AIP1.