Chemical inhibitor studies of polo-like kinase 1 in late mitosis and cytokinesis
- During cell division, chromosome segregation must be coordinated with cell cleavage so that cytokinesis occurs after chromosomes have been safely distributed to each spindle pole. Polo like kinase 1 (Plk1) is an essential kinase that regulates spindle assembly, mitotic entry and chromosome segregation but because of its many mitotic roles it has been difficult to specifically study its post-anaphase functions. Small molecule inhibitors were used to block Plk1 activity at anaphase onset and demonstrate that Plk1 controls both spindle elongation and cytokinesis. Plk1 inhibited cells failed to assemble a contractile ring and contract the cleavage furrow due to a defect in Rho and Rho-GEF localization to the division site. Plk1 inhibition did not affect anaphase A chromosome to pole movement but blocked anaphase B spindle elongation. Anaphase B is thought to result from the coordinated activities of microtubule-sliding motors that drive the poles further apart and changes in spindle microtubule dynamics. Plk1 is unlikely to control anaphase B through regulation of a spindle kinesin because inhibition of known motor proteins failed to recapitulate the Plk1 depletion phenotype. Instead, Plk1 inhibition caused a significant decrease in microtubule growth rate during metaphase and early anaphase, indicating a role for Plk1 in regulating microtubule dynamics. Consistent with an inhibition of microtubule growth rate, Plk1 inhibition reduced the rate of poleward microtubule flux in metaphase spindles and caused a reduction in metaphase spindle length that could be reversed by microtubule stabilization with taxol. These data suggest a model in which Plk1 accelerates microtubule growth during mitosis to maintain spindle length and drive anaphase B spindle elongation.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|2009, c2010; 2009
|Brennan, Ian Michael
|Stanford University, Department of Biochemistry
|Straight, Aaron, 1966-
|Straight, Aaron, 1966-
|Statement of responsibility
|Ian M. Brennan.
|Submitted to the Department of Biochemistry.
|Ph.D. Stanford University 2010
- © 2010 by Ian Michael Brennan
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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