Ricerc@Sapienza

Polymorphisms in the genome are responsible in humans for phenotypic differences and susceptibility to genetic disease. A significant fraction of molecular functional diversity in the human population is attributable to effects on protein function caused by non synonymous single nucleotide polymorphisms (nsSNPs). nsSNPs occur in the DNA coding region and induce a change in the amino acid sequence of the protein, namely single residue variation (SRV). Several investigations have addressed the effect of nsSNPs on protein stability, functions and interactions. SRV associated to nsSNPs may be related to variation of the kinetic parameters of enzymes, the DNA-binding properties of proteins that regulate transcription, the signal transduction activities of receptors, and the architectural roles of structural proteins. This project focuses on natural variants of the Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), a nuclear receptor that belongs to the superfamily of ligand inducible transcription factors, involved in several biological processes. PPARgamma is expressed in the adipose tissue and plays a key role in the regulation of lipid metabolism in mature adipocytes and macrophages. In addition, PPARgamma has been reported to be involved in several processes related to cellular differentiation and development and to carcinogenesis. In this study we will select nsSNPs resulting in PPARgamma variants, reported in databases such as COSMIC and OMIM, that are expressed in cancer tissues or that are related to alteration of metabolic control. The impact of PPARgamma nsSNPs on important pathways for the cell, such as cellular differentiation, apoptosis and propensity to tumorigenicity, will be analyzed and compared with the effect of the mutation on the protein structure and stability. The aim of the present study is to give insight the signaling network which orchestrates the regulation of cancer by PPARgamma variants activation in human cell lines.