Abstract

Dr Nhung My Thi HOANG

The chromosomal passenger complex (CPC) plays a key role in mitosis: controlling both chromosome segregation, spindle tension, anaphase onset and cytokinesis. The complex is composed of four proteins : INCENP, Aurora B kinase, Survivin and Borealin. Taking into account that Survivin is phosphorylated by Aurora B and plays a pivotal role in the complex, we have studied the phosphomimetic mutant SurvivinT117E. Survivin phosphorylation is required for anaphase onset and the phospho-mutant is poorly linked to the centromere. Moreover it exhibits a dominant negative function in cytokinesis, preventing abscission. In a search for Aurora kinase inhibitors we have identified a new class of Aurora B kinase inhibitors that prevents Histone H3 phosphorylation and impairs mitotic spindle checkpoint. Moreover these molecules prevent tumor cell proliferation. These inhibitors are novel tools for understanding CPC function and represent a new lead for the development of anti-cancer drugs. Survivin and Aurora B kinase, which are expressed exclusively in mitosis, are thus two druggable targets for new anti-mitotic therapies.

Host: Prof. Philipp Kaldis