The p53 family includes, in addition to the well-known tumour suppressor p53, two additional proteins, p63 and p73. These proteins are encoded by two different genes, each of them subjected to different activation modes. All family members have an essential role in either tumourigenesis or morphogenesis. The high degree of identity among the three protein sequences is mirrored by the existence of a common modular protein structure. All of them present a transactivation (TA), a DNA-binding (DBD) and an oligomerization (OD) domain, with a high level of sequence identity. Each gene gives rise to multiple isoforms because of differential promoter selection and alternative splicing at both 5′ and 3′ ends of the mRNA. Despite the homology, p53, p63 or p73 gene inactivation in mice gave rise to different phenotypes indicating that the proteins encoded by these genes play different roles. While p53 has the central function of tumour suppressor, both p63 and p73 are actively involved in development and differentiation. A complex set of post-translational modifications such as phosphorylation, acetylation, ribosylation, glycosylation, ubiquitylation and SUMOylation, with often-intertwined modes of action regulates p53 family members functions. Ubiquitylation and SUMOylation appear to affect transactivation ability, localization and stabilization of these transcriptional factors and to confer their timely regulated role during differentiation and development. In this chapter, the role of p53 family members will be described as well as the impact of ubiquitylation and SUMOylation on their functions. Moreover, other ubiquitin-like proteins have also been shown to regulate p53 family members activity. The interaction of the Ub/SUMO system with the complex regulation pathways of both tumour suppression and development guaranteed by the p53 family members constitutes an example of critical control machinery regulating cellular fate.
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