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• W2090098801 endingPage "e16307" @default.
• W2090098801 startingPage "e16307" @default.
• W2090098801 abstract "Background Highly Expressed in Cancer protein 1 (Hec1) is a constituent of the Ndc80 complex, a kinetochore component that has been shown to have a fundamental role in stable kinetochore-microtubule attachment, chromosome alignment and spindle checkpoint activation at mitosis. HEC1 RNA is found up-regulated in several cancer cells, suggesting a role for HEC1 deregulation in cancer. In light of this, we have investigated the consequences of experimentally-driven Hec1 expression on mitosis and chromosome segregation in an inducible expression system from human cells. Methodology/Principal Findings Overexpression of Hec1 could never be obtained in HeLa clones inducibly expressing C-terminally tagged Hec1 or untagged Hec1, suggesting that Hec1 cellular levels are tightly controlled. On the contrary, a chimeric protein with an EGFP tag fused to the Hec1 N-terminus accumulated in cells and disrupted mitotic division. EGFP- Hec1 cells underwent altered chromosome segregation within multipolar spindles that originated from centriole splitting. We found that EGFP-Hec1 assembled a mutant Ndc80 complex that was unable to rescue the mitotic phenotypes of Hec1 depletion. Kinetochores harboring EGFP-Hec1 formed persisting lateral microtubule-kinetochore interactions that recruited the plus-end depolymerase MCAK and the microtubule stabilizing protein HURP on K-fibers. In these conditions the plus-end kinesin CENP-E was preferentially retained at kinetochores. RNAi-mediated CENP-E depletion further demonstrated that CENP-E function was required for multipolar spindle formation in EGFP-Hec1 expressing cells. Conclusions/Significance Our study suggests that modifications on Hec1 N-terminal tail can alter kinetochore-microtubule attachment stability and influence Ndc80 complex function independently from the intracellular levels of the protein. N-terminally modified Hec1 promotes spindle pole fragmentation by CENP-E-mediated plus-end directed kinetochore pulling forces that disrupt the fine balance of kinetochore- and centrosome-associated forces regulating spindle bipolarity. Overall, our findings support a model in which centrosome integrity is influenced by the pathways regulating kinetochore-microtubule attachment stability." @default.
• W2090098801 created "2016-06-24" @default.
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• W2090098801 date "2011-01-28" @default.
• W2090098801 modified "2023-09-24" @default.
• W2090098801 title "Abnormal Kinetochore-Generated Pulling Forces from Expressing a N-Terminally Modified Hec1" @default.
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• W2090098801 doi "https://doi.org/10.1371/journal.pone.0016307" @default.
• W2090098801 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3030568" @default.
• W2090098801 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21297979" @default.
• W2090098801 hasPublicationYear "2011" @default.
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