Another fork in the road--life or death decisions by the tumour suppressor p53

Abstract

In response to cellular stress signals, the tumour suppressor p53 accumulates and triggers a host of antineoplastic responses. For instance, DNA damage activates two main p53-dependent responses: cell cycle arrest and attendant DNA repair or apoptosis (cell death). It is broadly accepted that, in response to DNA damage, the function of p53 as a sequence-specific transcription factor is crucial for tumour suppression. The molecular determinants, however, that favour the initiation of either a p53-dependent cell cycle arrest (life) or apoptotic (death) transcriptional programme remain elusive. Gaining a clear understanding of the mechanisms controlling cell fate determination by p53 could lead to the identification of molecular targets for therapy, which could selectively sensitize cancer cells to apoptosis. This review summarizes the literature addressing this important question in the field. Special emphasis is given to the role of the p53 response element, post-translational modifications and protein-protein interactions on cell fate decisions made by p53 in response to DNA damage.

Figure 1

Cellular stress induces p53-dependent responses. In response to cellular stress such as DNA damage, the p53 protein becomes stabilized. In the nucleus, p53 binds to specific promoters and activates transcription of its target genes. Additionally, p53 can also repress transcription of some of its targets. Depending on which genes are activated or repressed, p53 can induce cell cycle arrest, DNA repair, apoptosis and senescence, as well as regulate other processes such as energy metabolism. Independently of its effects on transcription, cytoplasmic p53 has been reported to trigger apoptosis, as well as necrosis. These responses ensure that damaged DNA is not replicated or transmitted to daughter cells, thus contributing to tumour suppression.

Figure 2

p53-binding site affinity and cell fate choice. DNA damage results in intracellular accumulation of p53 protein. It has been proposed that at lower levels of damage, p53 preferentially binds to high-affinity target genes, which tend to be involved in mediating cell cycle arrest. Prolonged exposure to DNA damage results in higher levels of p53, which ensures that more p53 is available to bind to weaker sites such as those found in many pro-apoptotic target genes. This view, however, seems to be oversimplified, as the affinity of p53 for some response elements is comparable regardless of whether they are located in genes mediating cell cycle arrest or apoptosis. Nevertheless, the model retains some traction. It remains reasonable that p53 target genes involved in cell cycle arrest are inherently programmed for rapid and short-lived responses. By contrast, pro-apoptotic targets would have a delayed and more sustained response to genotoxic stress. Bax, Bcl2-associated X.

Figure 3

Post-translational modifications on p53 dictate cell fate decisions. In response to DNA damage, p53 undergoes a series of post-translational modifications thought to be important in regulating p53 activity. Summarized here is a cartoon depicting the most relevant p53 modifications implicated in target gene selectivity and cell fate choice. For example, phosphorylation on Ser 46 and acetylation on Lys 120 enhances the preferential ability of p53 to transactivate genes that induce apoptosis. By contrast, acetylation and ubiquitination of Lys 320 have been implicated in mediating p53-dependent transcriptional activation of pro-arrest genes. Bax, Bcl2-associated X; DYRK2, dual-specificity tyrosine-phosphorylation-regulated kinase 2; E4F1, putative E3 ubiquitin-protein ligase; HIPK2, homeodomain-interacting protein kinase 2; hMOF, human males absent on the first (histone acetyltransferase); p53AIP, p53-regulated apoptosis-inducing protein 1; PCAF, p300/CBP-associated factor; PUMA, p53-upregulated modulator of apoptosis.

Figure 4

Interacting proteins contribute to target gene selectivity and cell fate choice by p53. The transcriptional activity of p53 on specific target genes can be influenced by protein–protein interactions of p53 and its co-factors. Interacting proteins or co-factor recruitment to p53 target gene promoters cooperate with p53 to determine which genes are activated and which cellular response is induced. (A) For example, p53 interactions with either Pin1 or ASPP1 and ASPP2 result in preferential activation of pro-apoptotic genes. By contrast, when bound to iASPP or Hzf, p53 preferentially activates genes that mediate cell cycle arrest. (B) Non-interacting co-factors might also have a role in determining which target genes are preferentially activated by p53. For example, RNAPII is found preloaded and enriched on pro-arrest p53 target genes. By contrast, CAS/CSE1L bound to pro-apoptotic p53 target gene promoters cooperates with p53 to induce an apoptotic response. ASPP, apoptosis-stimulating of p53 protein; CAS/CSE1L, cellular apoptosis susceptibility protein; HZF, haematopoietic zinc finger; iASPP, inhibitor of ASPP protein; Pin1, peptidyl-prolyl cis-trans isomerase; RNAPII, RNA polymerase II.