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The Functions of Mps1 and Its Substrate Centrin 2 in Centriole Assembly

Yang, Ching-Hui
http://rave.ohiolink.edu/etdc/view?acc_num=osu1284497208

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Molecular Genetics.
Centrosomes determine the polarity of the mitotic spindle and control chromosome segregation. Errors in centrosome duplication, such as the production of excess centrioles within a single cell cycle, lead to the production of abnormal spindles that cause chromosomes to distribute improperly, producing aneuploid cells such as those found in tumors. Mps1 is a protein kinase that regulates centrosome duplication; increasing Mps1 dosage results in centriole overproduction, whereas the depletion of Mps1 kinase activity causes the failure of centrosome duplication. However, it has been unknown how Mps1 is regulated or how it exerts its function. In this study we have explored the regulation of Mps1 and attempted to identify Mps1 substrates. Here, we show that Mps1 is regulated by degradation, and that Cdk2 regulates this degradation. Cdk2/cyclin A phosphorylates Mps1 at T468, and this phosphorylation protects Mps1 from proteasome-dependent degradation specifically at the centrosome, increasing centrosomal Mps1 levels and causing Mps1-dependent centrosome reduplication. Moreover, preventing Mps1 from being degraded at centrosomes causes centrosome reduplication in human cells in the absence of cyclin A. Furthermore, we have identified three Mps1 substrates, Cetn2, Cetn3, and HsSas-6 and identified three Mps1 phosphorylation sites within Cetn2. Overexpressing Cetn2 causes Mps1-dependent centriole overproduction that requires all three Mps1 phosphorylation sites. Wild type Cetn2 and a mutant mimicking constitutive Mps1 phosphorylation promotes centriole overproduction via different pathways. Moreover, the ability of a stable Mps1 lacking exons 12 and 13 to drive the production of mature centrioles requires Cetn2. Together, these data suggest that the regulation of Mps1 level at the centrosome and the phosphorylation of its substrates is important in the regulation of centrosome duplication.
Harold Fisk, PhD (Advisor)
Anita Hopper, PhD (Committee Member)
Paul Herman, PhD (Committee Member)
Stephen Osmani, PhD (Committee Member)
184 p.
Biology; Cellular Biology
Mps1; Cetn2; Cetn3; centriole overproduction; phosphorylation

Recommended Citations

Citations

  • Yang, C.-H. (2010). The Functions of Mps1 and Its Substrate Centrin 2 in Centriole Assembly [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1284497208

    APA Style (7th edition)

  • Yang, Ching-Hui. The Functions of Mps1 and Its Substrate Centrin 2 in Centriole Assembly. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1284497208.

    MLA Style (8th edition)

  • Yang, Ching-Hui. "The Functions of Mps1 and Its Substrate Centrin 2 in Centriole Assembly." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1284497208

    Chicago Manual of Style (17th edition)

osu1284497208
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This open access ETD is published by The Ohio State University and OhioLINK.