| Title: |
Expression Levels of a Kinesin-13 Microtubule Depolymerase Modulates the Effectiveness of Anti-Microtubule Agents |
| Authors: |
Schimizzi, Gregory V.; Currie, Joshua D.; Rogers, Stephen L. |
| Source: |
PloS One, 5(6) |
| Publication Year: |
2010 |
| Collection: |
Carolina Digital Repository (UNC - University of North Carolina) |
| Subject Terms: |
Microscopy; Kinesin; Science; Cell Biology/Cytoskeleton; Cell Biology/Cell Growth and Division; Fluorescence; DNA Primers; Microtubules; Animals; Cultured; Biochemistry/Chemical Biology of the Cell; Research Article; Drosophila; Base Sequence; RNA Interference; Cells; Medicine |
| Description: |
BackgroundChemotheraputic drugs often target the microtubule cytoskeleton as a means to disrupt cancer cell mitosis and proliferation. Anti-microtubule drugs inhibit microtubule dynamics, thereby triggering apoptosis when dividing cells activate the mitotic checkpoint. Microtubule dynamics are regulated by microtubule-associated proteins (MAPs); however, we lack a comprehensive understanding about how anti-microtubule agents functionally interact with MAPs. In this report, we test the hypothesis that the cellular levels of microtubule depolymerases, in this case kinesin-13 s, modulate the effectiveness of the microtubule disrupting drug colchicine.Methodology/Principal FindingsWe used a combination of RNA interference (RNAi), high-throughput microscopy, and time-lapse video microscopy in Drosophila S2 cells to identify a specific MAP, kinesin-like protein 10A (KLP10A), that contributes to the efficacy of the anti-microtubule drug colchicine. KLP10A is an essential microtubule depolymerase throughout the cell cycle. We find that depletion of KLP10A in S2 cells confers resistance to colchicine-induced microtubule depolymerization to a much greater extent than depletion of several other destabilizing MAPs. Using image-based assays, we determined that control cells retained 58% (±2%SEM) of microtubule polymer when after treatment with 2 µM colchicine for 1 hour, while cells depleted of KLP10A by RNAi retained 74% (±1%SEM). Likewise, overexpression of KLP10A-GFP results in increased susceptibility to microtubule depolymerization by colchicine.Conclusions/SignificanceOur results demonstrate that the efficacy of microtubule destabilization by a pharmacological agent is dependent upon the cellular expression of a microtubule depolymerase. These findings suggest that expression levels of Kif2A, the human kinesin-13 family member, may be an attractive biomarker to assess the effectiveness of anti-microtubule chemotherapies. Knowledge of how MAP expression levels affect the action of anti-microtubule drugs may prove useful ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://cdr.lib.unc.edu/downloads/sn00b529t?file=thumbnail; https://cdr.lib.unc.edu/downloads/sn00b529t |
| DOI: |
10.17615/1e34-ef14 |
| Availability: |
https://doi.org/10.17615/1e34-ef14; https://cdr.lib.unc.edu/downloads/sn00b529t?file=thumbnail; https://cdr.lib.unc.edu/downloads/sn00b529t |
| Rights: |
http://rightsstatements.org/vocab/InC/1.0/ |
| Accession Number: |
edsbas.4E784207 |
| Database: |
BASE |