P53 and Cell Death


The p53 transcription factor emerges not only as the most important tumour suppressor, but also as an intriguing scientific puzzle characterized by immense functional complexity. P53‐mediated apoptosis is a well‐established tumour suppression mechanism forming a critical barrier to tumourigenesis. Intense research into the mechanism of p53‐induced apoptosis revealed an involvement of p53 in the extrinsic and intrinsic cell death pathways, reactive oxygen species signalling and antisurvival responses. Notably, p53 exerts its effects by various direct and indirect mechanisms engaging transcriptional activation or repression of target genes as well as transcriptional independent modes of action. Importantly, more than 20 years of intense research has paved the way for a rational design of selective anticancer therapies aimed at restoration of p53 functionality in cancer cells.

Key concepts:

  • Apoptosis (programmed cell death) is a fundamental cellular process during development, maintenance of tissue homeostasis, and in cellular response to stress.

  • P53 function is compromised in most cancer cases either by direct mutations (50%) or by indirect mechanisms

  • P53 is a transcriptional factor that binds to specific target DNA sequences to either transcriptionally activate or repress genes.

  • P53 activates multiple apoptotic signalling pathways (extrinsic and intrinsic) thereby promoting an efficient apoptotic response.

  • The majority of pro‐apoptotic activities of p53 are mediated through the induction of specific apoptotic target genes, e.g. Bax, Puma and Noxa.

  • P53 also contributes in the mitochondrial outer membrane permeabilization due to its relocalization to mitochondra and interaction with Bcl‐2‐family members.

  • Harnessing p53 for cancer therapy is a promising strategy to combat cancer by reactivating pro‐apoptotic function in neoplastic cells.

Keywords: apoptosis; mutant p53; gain of function; transcriptional activity; cancer therapy

Figure 1.

Multiple signals activate p53 to induce various growth inhibitory responses. P53 tumour suppressor protein responds to diverse intarcellular (e.g. oncogene activation) and extracellular stimuli (e.g. nutrients deprivation) through activation of relevant downstream mechanisms (e.g. apoptosis) that act to protect cells from oncogenic transformation.

Figure 2.

Regulation of p53 by Mdm2. The amount of p53 protein is determined mainly by the rate of ubiquitin‐mediated proteolysis. Mdm2 is the E3 ligase of p53, inhibiting its activity and promoting it for degradation. In response to stress, the negative loop between p53 and Mdm2 is interrupted by proteins such as ARF, and by posttranslational modifications of p53 and Mdm2. ARF can be induced by oncogenes such as Myc or E1A resulting in p53 accumulation and apoptosis. Also, various posttranslational modifications of p53 and Mdm2 prevent Mdm2‐mediated degradation of p53.

Figure 3.

P53 activates the extrinsic and intrinsic cell death pathways. P53 activates the extrinsic pathway by directly inducing the expression of death receptors, such as Fas/CD95 or DR‐5 as well as caspases 8 and 6. P53 also activates the intrinsic pathway where p53 act at multiple levels mainly through transactivation of multiple genes associated with the mitochondria as well as downstream factors such as: Apaf‐1. Small yellow circles mark p53 target genes, whereas an orange small circle indicates p53‐repressed gene.

Figure 4.

Structure of p53 family members and their roles in growth suppression and development. The p53 family consists of p53, p63 and p73, which have similar structure and share homology in major domains such as transactivation domain (TA), (DBD), proline‐rich domain (PR) and oligomerization domain (OD). P63 and p73 also contain additional proline‐rich domain (PR) and (SAM). The involvement of each member in growth suppression and development is indicated.

Figure 5.

Strategies for activation of p53 in cancer cells. Wild‐type p53 can be activated by inhibition of the interaction between p53 and Mdm2 using Nutlins and RITA. Mutant p53 can be reactivated using small molecules such as CP‐31398, PRIMA‐1 or MIRA. CDB3 is able to shift the equilibrium existing between wild‐type p53 and muatant p53 towards functional p53. P73 chemosensitivity can be restored by exposure to RETRA or 37AA, if its activities are inhibited through sequestration by mutant p53 or is APP, respectively.



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Further Reading

Campisi J and D'adda Di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nature Reviews. Molecular Cellular Biology 8(9): 729–740.

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Wolyniec, Kamil, Haupt, Sue, and Haupt, Ygal(Dec 2009) P53 and Cell Death. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021824]