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p53 is a transcription factor involved in tumour suppression encoded by the TP53 gene on chromosome 17. This cellular phosphoprotein regulates a number of genes, including those that initiate apoptosis, inhibit angiogenesis and cell cycle progression. 

These genes regulated by p53 play an important role in the cellular response to stress and the prevention of mutations which can lead to cancer.

Such is the importance of p53 that in nearly 50% of all human tumours a mutation in the TP53 gene is present; this suggests that a functional form of p53 is extremely important in the prevention of oncogenesis.

p53 in the normal cell

P53 is present in non-cancerous cells at extremely low levels and its quantities are highly controlled by Murine double minute 2 (Mdm2) and Jun N-terminal Kinase (JNK), its negative regulators. JNK is also involved in neurodegeneration, inflammation and cell differentiation whereas the predominant function of Mdm2 appears to be the regulation of p53. 

Mdm2 binds to p53 protein in dividing cells thereby promoting ubiquitination (the attachment of Ubiquitin protein which acts as a signal for degradation) which, as a consequence, leads to the rapid degradation of p53. JNK regulates p53 in a similar manner to Mdm2 whereby it binds to p53, preventing it from exerting its transcriptional effects. JNK negatively regulates levels of p53 in cells maintained in the G0 stage of the cell cycle. 

This negative regulation and the fact p53 has an extremely short half-life means that, in the normal cell, p53 exists latently in minute quantities, until stress upon the cell ceases its regulation.  

How does p53 prevent oncogenesis?

Upon cell stress such as DNA damage, oxidative stress, ribonucleotide depletion or the activation of oncogenes, specific pathways are triggered (depending on the type of cell stress) which lead to two main events: the stabilisation of p53 to increase its half-life and numerous modifications (including phosphorylation and dephosphorylation of specific amino acid residues and altered protein-protein interactions) that inactivate or severely decrease the negative regulation of p53. These lead to an accumulation of p53 in the nucleus. p53 is then able to bind to DNA, via its DNA-binding core domain, and promote the transcription of genes involved in preventing oncogenesis. The activation of p53 is illustrated below.

 These genes initiate DNA repair when it is damaged, cease the cell cycle (at G1 or G2) in order to prevent any mutated cells from dividing, inhibit angiogenesis to avoid tumour cells receiving the oxygen they need to thrive and instruct the cell to undergo apoptosis if repair is not possible. 

P53 also activates genes involved in cell differentiation along with regulating targets involved in cell senescence. 

Therefore, p53 is an extremely important factor in preventing the development of cancer as it regulates pathways involved in multiple different mechanisms that preclude tumour formation.

The inhibition of p53 is illustrated below.

What goes wrong with p53 in cancer?

Cancerous cells which have formed as a result of a mutation in the TP53 gene lack a completely functional form of p53.

Numerous types of mutations in the gene coding for p53 can lead to the development of cancer however, it has been established that the vast majority (95%) of these mutations in TP53 occur in the central region of the gene, a region which codes for the DNA binding element of p53 protein.

The DNA binding element of p53 is crucial for its function, as, being a transcription factor, it must interact with DNA in order to promote transcription of genes involved in preventing the development of cancer.

Mutations in other regions of p53, such as in the C- and N-termini, are also found in tumour cells.

Furthermore, p53 function can be lost in tumor cells even with a completely normal un-mutated TP53 gene. In these tumour cells, mutations in the regulators of p53 or mutations in the responses of cells to stress can result in p53 being permanently inactivated, leaving it unable to exert its transcriptional activities and appear like a loss of function mutant.

Mutations in p53 are most often the result of a single amino acid change (missense mutation); this feature is characteristic for p53. In contrast, many other tumour suppressor proteins are more liable to frameshift mutations.

These single amino acid changes not only stop p53 from exerting its anti-oncogenic role but can also lead to ‘gain of function’-oncogenic activities, including promoting up-regulation of genes involved in cell cycle progression and cell migration.

In this way, a single amino acid mutation can change p53 from preventing the formation of tumours to actively promoting their growth.


Therapeutic potential of p53 manipulation

Animal studies have shown that the biological targeting of p53 causes it to return to normal function, halting tumourigenesis either by apoptosis or senescence.

There are likely to be specific therapies aimed at restoring p53 by a missense mutation back to the wildtype form, in addition to treatments that return any over expression of p53 repressors to a normal level. For example, reactivation of p53 anti-angiogenic activity in mice, by injection of nanoparticles loaded with p53 DNA, proved successful in experiments by Prabha, S et al.; providing a potential therapy for inhibition of human tumour growth in the future.

Numerous necessary co-factors for p53-mediated apoptosis are being newly discovered, and therapies targeted at these molecules are thought to be therapeutically viable in the future to induce apoptosis of tumour cells.

Although p53-targeted therapies are not currently available, there is a growing interest of research in this area.It appears likely that many future cancer therapies will restore the wildtype function of p53 to finally cure cancer.



The author would like to thank Michael Barron LLB for his critical review of this article.  


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