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Mps1 kinase signaling in mitosis

By N. Jelluma

Abstract

Chromosomal instability (CIN), a feature widely shared by cells from solid tumors, is caused by occasional chromosome missegregations during cell division. Maintenance of chromosomal stability relies on coordination between various processes that are critical for proper chromosome segregation in mitosis. Equal segregation of chromosomes during cell division depends on a coordinated effort to attach and align all chromosomes on the metaphase plate (biorientation) before onset of anaphase. The mitotic checkpoint halts cell-cycle progression until all paired sister chromatids are bioriented and aligned on the metaphase plate. The mitotic checkpoint responds to lack of attachment of kinetochores to spindle microtubules or lack of tension between kinetochores of sister chromatids, and depends on several kinases including Bub1, BubR1, and Mps1. Loss of checkpoint function results in gross chromosome missegregations and eventually cell death. However, increased rates of CIN in cells derived from human tumors have been reported. It has been suggested through several in vivo model systems that weakening of the mitotic checkpoint contributes to carcinogenesis, or may even induce spontaneous tumor formation. Since tumor cells cycle very rapidly, the mitotic checkpoint is an interesting target for cancer treatment. Additionally, the CIN phenotype may sensitize cells to cell death by induction of extra chromosome missegregations through mitotic checkpoint inhibition. This could potentially result in selective killing of CIN tumors, while sparing healthy tissue. A possible downside to this approach is that partial inhibition could sensitize healthy tissue to tumorigenesis, or even induce tumor formation. It is therefore important to study the mechanism of checkpoint functioning extensively. The research described in this thesis focuses on Mps1 biology since Mps1 is an evolutionary conserved protein with a conserved essential function in the mitotic checkpoint. The fact that Mps1 is a protein kinase makes it a candidate contributor to amplification of the checkpoint signal and its activity could enable a faster switch from an active checkpoint to silencing of the checkpoint compared to for example protein degradation or translation events. With regards to cancer, Mps1 could be a good therapeutic target, especially because it is a kinase that can potentially be inhibited in the patient through administration of an inhibitory chemical compound. At the onset of the studies described in this thesis, not much was known about the upstream regulation and downstream signaling of Mps1. The work presented in this thesis provides new mechanistic insights on Mps1 signaling in the mitotic checkpoint and reveals a function of Mps1 in coordinating chromosome biorientation and the mitotic checkpoint. Many aspects of mitotic checkpoint signaling and the precise role of Mps1 herein however remain to be uncovered. Our findings contribute to the basis for future fundamental research in the field of mitosis and mitotic checkpoint signaling, and to further possibilities to explore the mitotic checkpoint as a possible target for cancer treatment

Topics: Econometric and Statistical Methods: General, Geneeskunde (GENK), Geneeskunde(GENK)
Publisher: Utrecht University
Year: 2010
OAI identifier: oai:dspace.library.uu.nl:1874/44439
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