Targeting Mitotic Ubiquitin Receptor Protein Ubash3b For Cancer Therapies
Reference : PhD Izabela Sumara
Publication de l'offre : 26 janvier 2018
Defects in mitosis lead to aneuploidy and tetraploidy, which are highly prevalent in cancer disease and deregulated expression of mitotic factors is a common trait of various cancers. Post-translational modifications of proteins by attachment of ubiquitin regulate mitotic progression. The ubiquitin-binding proteins serve as intracellular receptors for ubiquitin signals and determine the fate of ubiquitylated substrates.
Recently, we characterized a novel, mitotic ubiquitin receptor UBASH3B that acts on the critical mitotic kinase Aurora B and controls its subcellular localization. Redistribution of Aurora B from chromosomes to microtubules by UBASH3B controls timing and fidelity of chromosome segregation in human cancer cells. We believe that UBASH3B represents an ideal drug candidate for future cancer therapies. UBASH3B levels are upregulated in patients suffering from aggresive cancers and downregulation of UBASH3B specifically in cancer cells leads to their apoptotic death due to impaired localization of Aurora B but does not affect primary cells. Thus, inhibition of UBASH3B may represent an attractive therapeutical strategy for cancer disease.
Therefore, we have identified a small molecule inhibitor UBASHIN that can specifically bind to and interfere with the function of UBASH3B during mitosis. Importantly, UBASHIN treatment mimicks UBASH3B downregulation by siRNA and leads to defects in Aurora B localization and in chromosome segregation. UBASHIN treatment inhibits the interaction of UBASH3B with Aurora B and its regulator the microtubule kinesin protein MKlp2. Moreover, our preliminary data suggest that UBASHIN selectively causes death of cancer cells that express high levels of UBASH3B but not of primary cells.
The aim of this project is to characterize in detail the molecular mechanisms underlying UBASHIN action and to confirm its anti-tumor activity in animal models. We hope that this research will, in a long term, establish UBASH3B as antimitotic therapeutic target for cancer disease.
Date limite de candidature : 1 novembre 2018