MCAK and Stathmin Upregulationin Breast Cancer Cells: Etiology and Response to Pharmacologic Reagents

Abstract

Abstract : The goal of this study is to assay the role that two modulators of microtubule dynamics, Mitotic centromere-associated Kinesin (MCAK) and Op18/stathmin (stathmin) play in the development of cancer. These proteins are elevated in aggressive breast cancer tumors and changes in the levels and activity of these proteins are correlated with aneuploidy and invasiveness. In addition to our previously discovered C-terminal regulation, we have uncovered another major regulatory mechanism to control microtubule dynamics through MCAK activity. Phosphorylation of conserved serine residues in the neck and N-terminus of MCAK by Aurora B kinase inhibits its activity. It is likely that phosphorylation and dephosphorylation controls MCAK's activity during mitosis and also, via other kinases, during interphase. We have also identified two other Kin I kinesins which regulate microtubule dynamics in cultured cells and are likely to be regulated by kinases and phosphatases. These regulatory kinases also control stathmin activity in cells. Regulation of these proteins via cascades of kinase and phosphatase activities opens up a major new area for the application of therapeutics to control microtubule dynamics and augment existing cancer therapies that target microtubules. These data, which were reported as preliminary in Annual Report 2003 are now published or close to submission.