CHARACTERIZATION OF THE ROLE OF THE PROLYL-ISOMERASE PIN1 IN REGULATING P73 FUNCTIONS

Differentiation and programmed cell death are essential processes for multicellular organisms. Both of them involve the activation of aspecific genetic program which, if not properly controlled, may cause several pathological disorders, among them neurodegenerations such as Alzheimer’s disease. Among the proteins involved in controlling these processes a relevant role is played by p73 and p63, members of the p53-like protein family. In contrast to p53, whose role is crucial for tumor suppression, p73 and p63 seems to be involved in neuronal development and cellular differentiation. Not much is known about the mechanisms controlling the activation of these proteins following different types of stimuli, although clear evidences emerged about an involvement of post-translational modifications and interaction with specific protein. With this proposal we aim at understanding the role played in p73 regulation during neuronal differentiation and following several genotoxic insults by a protein called Pin1. Interestingly, Pin1 can recognize on its interacting proteins specific amino acids which have been phosphorylated and provokes, through its enzymatic activity, conformational changes which contributes to the activation of the substrates. Notably, recent evidences pointed toward a role of Pin1 in Alzheimer’s disease. Following the biochemical characterization of the Pin1/p73 interaction during differentiation and after DNA damage, we will analyse the role of Pin1 on the transactivation activity of p73 and on its ability to modulate both cell death and differentiation. We are confident that this analysis will contribute to the understanding of the physiological role of both p73 and Pin1 during neuronal differentiation and cell death and will represent a platform for future studies on the genesis and progression of pathological conditions, such as Alzheimer’s disease.