THE CONTROL OF TGF-BETA SIGNALS IN P63-LINKED GENETIC DISEASES AND MUSCLE ATROPHY: UNEXPECTED EFFECTORS, NOVEL MODULATORS AND FRESH PATHOGENETIC MECHANISMS

Cells communicate constantly with each other. They exchange special signals, including proteins called growth factors. These molecules regulate cell behaviour, that is, they decide whether the cell must proliferate, differentiate or die. When a genetic defect unbalances the normal equilibrium in these events, then a disease arises.The defects we are dealing in this Telethon grant concern a family of "signals", the TGF-beta family. These molecules control multiple physiological processes and their alterations (giving rise to extra or reduced signaling) stand at the base of several rare genetic defects in humans as well as of common disorders, such as hypertension and fibrosis.In a recent work, we unveiled that p53, a gene very well known for protecting us from tumors, cooperates with TGF-beta in restraining cell growth.In this project we propose to explore the function of p63 in the TGF-beta system. p63 is a "twin" of p53. But surprisingly, p63 is not following p53's steps for cancer suppression, but rather it operates in cell differentiation, during embryonic development and in adult stem cells. Indeed, p63 is not mutated in cancers but in a series of human disorders, and here we plan to investigate whether these mutations affect the ability of p63 of working together with the TGF-betas. This may provide a new interpretative clue of the pathogenesis of p63-linked and other diseases.moreover, we plan to study the function of a new gene that we recently identified, in preventing muscle atrophy that characterizes several neuromuscular defects and other diseases, such as AIDS or immobility induced cachexia.