Hase1- the connection between tumor suppression and degradation of misfolded proteins

Abstract

Hace1 is a tumor suppressor, E3-ligase that is involved in protein folding and targeting misfolded proteins for degradation. The unfolded protein response (UPR) is proposed to be the link between the involvement of Hace1 in protein folding and cancer as tumor cells suffer from high unfolded protein load. Upon UPR activation, chaperons are up-regulated and misfolded proteins are either refolded or marked for degradation by the ubiquitin-proteosome system. UPR leads to apoptosis of untransformed cells and is growth promoting in transformed cells, hence a paradox. I propose to determine whether the tumor suppressor activity of Hace1 is related to reduction of misfolded protein load and reduced activation of the UPR. Two approaches will be taken to address this question: 1. Unfolded protein load will be induced in transformed and untransformed cells and the role of Hace1 in misfolded protein handling and cell survival will be determined. 2. Unfolded protein loads in live transformed an 'normal' cells will be determined by the diffusion parameters of RFP and the role of Hace1 in handling unfolded proteins in these cells will be studied. In my PhD thesis I studied the micro- and macro-localization of Ras in the cell using biophysical methods. My studies provided me with a strong basis in using a biophysical approach to study protein dynamics in live cells, which will contribute to the development of the novel method needed to determine unfolded protein load in live cells. By studding Hace1 I will have the opportunity to apply my skills to study how cells cope with physiological challenges and get acquainted with new approaches necessary to precede with my academic career.