Investigating an Evolutionarily Conserved Role for the Tousled-like Kinase in Genome Stability and as a Novel Target for the Treatment of Ovarian Cancer.

摘要

In this project we are utilizing C. elegans and normal and cancer- derived human cell lines to interrogate the role of the Tousled-like kinase family in mitotic spindle dynamics. Thus far, our C. elegans studies support our hypothesis that phosphorylation of TLK-1 by the CHK1 and Aurora B kinases promote the localization of TLK-1 to mitotic chromosomes where it facilitates spindle assembly and chromosome congression. In addition, we discovered that TLK-1 has an unexpected role in mitotic spindle positioning in the early C. elegans embryo. Since spindle positioning is dependent on microtubule-based mechanisms, this finding further supports our contention that TLK-1 is a microtubule-regulatory protein. In our human cell studies, we discovered that depletion of human Tlk1 has a dramatic effect on mitotic spindle assembly and microtubule behavior in a cancer cell line. Furthermore, human Tlk1 may also functionally inhibit the epithelial to mesenchymal transition (EMT). Both of these findings are extremely exciting in that human Tlk1 has an essential role in mitotic spindle assembly but also appears to regulate microtubule dynamics and the cytoskeleton more broadly. A role for Tlk1 in preventing EMT has never been reported and opens up an entirely new avenue of inquiry into this multi- faceted kinase family.