Biochemical heterogeneity and developmental varieties in T-cell leukemia |
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| Authors: | Arup K Chakraborty Jeroen P Roose |
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| Institution: | 1.Departments of Chemical Engineering, Chemistry, Physics and Biological Engineering; Massachusetts Institute of Technology; Cambridge, MA USA;2.Institute of Medical Engineering & Science; Massachusetts Institute of Technology; Cambridge, MA USA;3.Department of Anatomy; University of California, San Francisco; San Francisco, CA USA |
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| Abstract: | During mitosis, chromosomes undergo dynamic structural changes that include condensation of chromosomes – the formation of individual compact chromosomes necessary for faithful segregation of sister chromatids in anaphase. Polo-like kinase 1 (Plk1) regulates multiple mitotic events by binding to targeting factors at different mitotic structures in a phosphorylation dependent manner. In this study, we report the identification of a putative ATPase that targets Plk1 to chromosome arms during mitosis. PICH (Plk1-interacting checkpoint “helicase”) displays a temporal localization on chromosome arms and kinetochores during early mitosis. Interaction with PICH recruits Plk1 to chromosome arms and disruption of this interaction abolishes Plk1 localization on chromosome arms. Moreover, depletion of PICH or overexpression of PICH mutant that is defective in Plk1 binding or ATP binding causes defects in mitotic chromosome compaction, formation of anaphase bridge and cytokinesis failure. We provide data to show that both PICH phosphorylation and its ATPase activity are required for mitotic chromosome compaction. Our study provides a mechanism for targeting Plk1 to chromosome arms and suggests that the PICH ATPase activity is important for the regulation of mitotic chromosome architecture. |
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| Keywords: | cancer heterogeneity CyTOF RasGRP1 Ras signaling T-cell leukemia computational models kinase inhibitor molecular therapy |
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