(from the application): The polo family of protein kinases is now known to have a critical role in proliferation. In higher eukaryotes, flies, and yeast polo kinase homologues are essential for cell cycle progression through M phase. In mammals, distinct polo kinases -for example, Snk-are also expressed early in the cell cycle. The mammalian enzymes, particularly Plk and Snk are the focus of the studies proposed in this application. IN addition to the catalytic kinase domain, polo kinases have a conserved sequence in the C-terminus, denoted the polo box. Polo box mutations disrupt the cellular localization observed with wild-type Plk and compromise Plk mitotic functions. Polo box interacting proteins will be identified and their potential to influence centrosome biogenesis and function, as well as septin localization and organization, will be determined. A general search for Snk and Plk substrates will be conducted by screening expression libraries and by engineering these enzymes to attain the capacity to utilize ATP analogues that will not be used efficiently by other kinases. In order to more precisely characterize Snk functions, embryonic stem cells will be generated with a targeted gene disruption. These cells will be used to obtain mice with germline transmission in order to determine the potential role of Snk in embryonic development. These studies have direct relevance to cancer, as the ordered segregation of chromosomes to two daughter cells requires unimpaired Plk function. Until recently, aneuploidy, the condition in cancer cells in which they display an abnormal number of chromosomes, was considered a consequence, rather than a cause, of the malignancy. However, recent studies suggest aneuploidy can cause cancer. Centrosomes play a critical role in the maintainance of the integrity of the human genome. Aberrant centrosome structure and aneuploidy are tightly correlated in advanced tumors. The studies proposed here address the molecular events controlled by Plk involving centrosome duplication and initiation of cleavage furrow formation and the potential of Snk to influence these and other events in specific cell types.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDF-1 (01))
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Zatz, Marion M
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Harvard University
Schools of Arts and Sciences
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Yim, Hyungshin; Erikson, Raymond L (2011) Regulation of the final stage of mitosis by components of the pre-replicative complex and a polo kinase. Cell Cycle 10:1374-7
Yim, Hyungshin; Erikson, Raymond L (2010) Cell division cycle 6, a mitotic substrate of polo-like kinase 1, regulates chromosomal segregation mediated by cyclin-dependent kinase 1 and separase. Proc Natl Acad Sci U S A 107:19742-7
Yim, Hyungshin; Erikson, Raymond L (2009) Polo-like kinase 1 depletion induces DNA damage in early S prior to caspase activation. Mol Cell Biol 29:2609-21
Lei, M; Erikson, R L (2008) Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint. Oncogene 27:3935-43
Zimmerman, Wendy C; Erikson, Raymond L (2007) Finding Plk3. Cell Cycle 6:1314-8
Liu, Xiaoqi; Erikson, Raymond L (2007) The nuclear localization signal of mitotic kinesin-like protein Mklp-1: effect on Mklp-1 function during cytokinesis. Biochem Biophys Res Commun 353:960-4
Zimmerman, Wendy C; Erikson, Raymond L (2007) Polo-like kinase 3 is required for entry into S phase. Proc Natl Acad Sci U S A 104:1847-52
Zhou, Tianhua; Zimmerman, Wendy; Liu, Xiaoqi et al. (2006) A mammalian NudC-like protein essential for dynein stability and cell viability. Proc Natl Acad Sci U S A 103:9039-44
Liu, Xiaoqi; Lei, Ming; Erikson, Raymond L (2006) Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol Cell Biol 26:2093-108
Tang, Jiabin; Erikson, Raymond L; Liu, Xiaoqi (2006) Checkpoint kinase 1 (Chk1) is required for mitotic progression through negative regulation of polo-like kinase 1 (Plk1). Proc Natl Acad Sci U S A 103:11964-9

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