FUNCTIONAL ROLE OF THE HIPK2/P53 INTERACTION IN DIFFERENTIATION AND DEVELOPMENT

Our studies aim at understanding the molecular mechanisms through which somatic cells reach their physiological state of complete differentiation. The comprehension of these mechanisms is the basis for understanding the pathogenesis of congenital and acquired diseases. In the past years, with the Telethon support, we have discovered that the p53 gene, thought to be relevant only in tumors, is indeed an important regulator of skeletal muscle differentiation. Starting from this finding, we have look for p53 partners in the development of mouse embryos. We have found that p53 physically and functionally interacts with a protein named homeodomain-interacting protein kinase 2 (HIPK2). The relevance of this finding is that it is the first time that a protein known as an oncosuppressor is indeed able to interact, at least indirectly, with a class of proteins, the homeobox proteins, whose role is specific for the developmental process of many multicellular organisms, from flies to humans. Mutations of homeobox proteins can cause several congenital diseases (e.g., mutations of the human homeobox NKX2-5 can cause congenital heart disease with atrial septal defects and severe atrioventricular conduction block, or the tetralogy of Fallot). Our finding suggests that some homeobox proteins can be regulated by p53 in their expression or function. In the presented project, we propose to study the type and the biological functions of these interactions by creating mouse models that lack the key protein HIPK2 or both p53 and HIPK2 proteins, and by interfering with the functions of this two proteins in muscle, heart and neural cells in culture. This type of study should allow the understanding of previously unsuspected relationships between proteins strictly related to differentiation and development (Homeobox) with proteins known to control the stability of the genome (p53).