Mitosis: Molecular Regulatory Networks and Potential Therapeutic Targets in Mammalian Cells.
Mitosis is the most critical time in the life of a cell. A dramatic reorganization of cellular structures takes place within a relatively short time to enable the organization and function of the mitotic apparatus, which is essential to drive even chromosome segregation to daughter cells. Mis-organization or mis-function of the mitotic apparatus, if not counterselected or corrected in the cell in which they occur, can give rise to chromosome mis-segregation and initiate a condition of genetic instability, representing a hallmark of cancer cells.
Complex regulatory networks are in place to ensure proper assembly and function of the mitotic apparatus in each cell cycle. Wefocus on the networks mediated by the GTPase Ran and the kinase Aurora-A. We use a combination of functional approaches and advanced imaging techniques to clarify their mechanisms of spatial and temporal control of mitosis. In recent work, we have identified new roles of the Ran GTPase network in the interaction between the spindle microtubules and mitotic kinetochores. In parallel, we have identified a new mechanism regulating Aurora-A protein stability, which may represent a novel route to Aurora-A deregulated expression in cancer cells.
The mitotic apparatus, in addition to being a potential source of errors in cancer cells, can be viewed as an ‘Achille’s heel’ that can be targeted to arrest cell division in cancer. A related aspect is being developed in collaborative studies to develop molecules that can destabilise the mitotic apparatus and to characterise the response of cancer cells to these molecules.