ation, p53 is systematically deregulated ” in cancers and other pathologies involving abnormal cell proliferation. P53 is a multifunctional 393-residue protein. The central core domain constitutes a single folded unit that bears the sequence-specific DNA-binding activity of p53. The core domain is flanked by modulatory regions including an Nterminal transactivation domain, a proline-rich domain, a helical tetramerisation domain and a C-terminal regulatory domain. These regions modulate the transcriptional activity of the core domain in response to various ligands or modifications such as phosphorylation or acetylation. The three-dimensional structure of the core domain bound to its double-stranded DNA target has unravelled the structural basis of p53 transcriptional activity. Genotoxic stress-induced p53 accumulation mainly results from post-translational stabilisation. Therefore, both the physiological and pathological mechanisms of p53 turnover have been extensively studied. The cellular MDM2 protein, first known as a transcriptional target of p53, was found to 
“7069713 act as a E3 ubiquitinligase, which transfers ubiquitin onto p53, thereby targeting it to proteasome-mediated degradation. Perturbation of MDM2 function leading to enhanced degradation of p53 is a key event in numerous cancers. Enhancement of p53 degradation has also been recognised as one of the strategies used by oncoviruses that stimulate cell proliferation for the sake of their own life cycle. Adenoviral proteins E1b 55k and E4 34k have been shown to form a stable complex with p53 leading to its enhanced ubiquitination and subsequent proteasome-mediated October 2011 | Volume 6 | Issue 10 | e25981 p53 Degradation Mediated by HPV E6 degradation. The E6 oncoprotein of “high-risk”HPV types has also been demonstrated to catalyse the ubiquitinmediated degradation of p53. E6 is a small protein of about 150 residues composed of two 70-residue zinc-binding domains. E6 interacts with E6AP, a 850-residue E3 ubiquitin-ligase. E6AP contains an E6-binding site within a central 18-residue stretch comprising the “LxxLL”motif that is found in several other targets of E6. p53 has been proposed to contain two distinct E6-binding sites. The Cterminal modulatory domain has been suggested to contain a primary E6-binding site recognised by all E6 proteins of both low- and high-risk HPV types, but this interaction has no role in E6-induced p53 degradation. The core domain of p53 appears to contain a secondary E6binding site restricted to E6s of high-risk HPVs. E6 binding to this secondary site is E6AP-dependent and is required for p53 ubiquitination and subsequent degradation. The precise location of this site within the p53 core domain structure is still unknown. Li and Coffino showed that aminoacids 100150 of p53 contain a degradation domain and hypothesized this region as the second binding site for high risk E6. Additionally, Gu et al. proposed that p53 has a unique sequence element within the core domain that acts as a signal for MDM2mediated degradation and the binding of oncoproteins, which direct p53 degradation towards proteasome pathway. This secondary site was also required for E6/E6AP-mediated p53 ubiquitination and subsequent degradation, whereas the primary site was dispensable for these activities. More recently a secondary MDM2 binding site was suggested to exist in the Indirubin-3′-oxime flexible loop which links S9S10 b-strands of the p53 core domain and proposed as a regulatory element modulating p53