IDENTIFICATION OF THREE NOVEL REGULATORY PATHWAYS INVOLVED IN THE DOWN-REGULATION OF P63 PROTEIN LEVELS

One way to regulate protein functions is by post-translational modification. Post-translational modifications have an important role in the regulation of biological activity of the protein because they allow both to extend the range of functions of a protein and to monitor the activity and determine the activation or inactivation of a protein. The most common protein post-translational modifications include ubiquitylation, phosphorylation and acetylation play an essential role in cellular functions such as cellular differentiation, apoptosis, DNA repair, antigen processing, and stress response. Under particular conditions abnormal post-translational modifications were found in many diseases like: Alzheimer’s disease, Parkinson’s disease, induction of different cancer and others. These abnormal post-translational modifications are permanent and can cause loss or alteration of protein function by changing enzyme activities or capacity aggregation (Stadtman and Levine 2000; Shacter 2000). p63 protein stability is regulated by different protein modifications such phosphorylation, ubiquitylation and sumoylation. p63 is known to be degraded by ubiquitin-mediated proteasomal degradation, the E3 ubiquitin ligase NEDD4-like, ubiquitin protein ligase Itch and ubiquitin-like protein SUMO-1 have been shown to directly interact with p63 and regulate p63 protein stability (Ghioni et al. 2005; Rossi at al. 2006; Rossi et al. 2006) suggest the importance of regulating p63 to tune its biological activity. During my PhD thesis we found three novel and distinct mechanisms that are involved in the regulation of the p63 protein levels; all these mechanisms induce p63 degradation. We demonstrated that these mechanisms are relevant in different physiological contexts and that they are involved in the regulation of p63 biological function. 1. MDM2-Fbw7 pathway contribute to reduce ΔNp63α protein levels during keratinocytes differentiation and upon DNA-damage induced by UV exposure and adriamycin treatment. 2. TRIM8 plays a role in enhancing p53 anti-oncogenic activity and at the same time down-modulate oncogenic ΔNp63α activity. 3. Hipk2 phosphorylates and promotes proteasomal degradation of ΔNp63α to enable an effective DNA-damage response induced by genotoxic drugs. All these evidences indicate that regulation of p63 protein stability is a key mechanism to control p63 activities, in particular during epithelia differentiation and in response to genotoxic agents. The knowledge and the identification of the molecular mechanisms governing p63 regulation under physiological context might be fundamental for understanding the pathogenesis of human syndromes associated to p63 mutations and the mechanism by which p63 promotes disease development. We hope that future studies focusing on the mechanisms involved in p63 protein regulation might increase our knowledge on the p63 role in tumorigenicity and in response to anti-cancer therapy to improve anti-cancer therapies.