p53 is situated at the crossroads of a network of signalling pathways that are essential for cell growth regulation and apoptosis induced by genotoxic and non-genotoxic stresses (Melino et al., 2002; Vogelstein et al., 2000; Vousden & Lu, 2002).
In normal unstressed cells, the level of p53 protein is downregulated via the binding of proteins such as MDM2, COP1, PIRH2 or JNK that promote p53 degradation via the ubiquitin/proteasome pathway. As most of these genes are up regulated by p53, this lead to a regulation loop that will keep p53 level very low in a normal cells.
After genotoxic or non-genotoxic stresses, activation of p53 is a two steps process. First p53 protein level is increased via the inibition of its interaction with mdm2 and the other negative regulators. Overtranslation of p53 RNA is a complementary that will also ensure p53 accumulation. Second, a series of modulator (kinases, acetylases) will activates p53 transcriptional activity.
A plethora of proteins have been found to bind various regions of p53 in order to regulate the specificity of its activity.
Downstream signalling includes a large series of genes that are activated by the transactivating properties ofp53. This occurs via specific DNA binding of the p53 protein to a p53 response element (p53 RE) that isfound either in the promoter or in the intron of target genes (El-Deiry et al., 1992; Tokino & Nakamura, 2000).
Regardless of the type of stress, the final outcome of p53 activation is either cell cycle arrest and DNA repair or apoptosis, but the mechanism leading to the choice between these fates has not yet been elucidated (see (Vousden & Lu, 2002) for discussion).
The p53 pathways has been conveniently divided into five parts (Levine et al., Cell Death and Diffrentiation (2006), 1-10).
i)The stress signals that activate the pathway
ii) The upstream mediators that detect and interpret the upstream signals.
iii) the core regulation of p53 through its interaction with several proteins that modulate its stability
iv) the downstream events, mainly transcriptional activation or protein protein interactions
v) The final outcome, growth arrest, apoptosis or DNA repair.