Document Detail


Low-dose laulimalide represents a novel molecular probe for investigating microtubule organization.
MedLine Citation:
PMID:  22871740     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Laulimalide is a natural product that has strong taxoid-like properties but binds to a distinct site on β-tubulin in the microtubule (MT) lattice. At elevated concentrations, it generates MTs that are resistant to depolymerization, and it induces a conformational state indistinguishable from taxoid-treated MTs. In this study, we describe the effect of low-dose laulimalide on various stages of the cell cycle and compare these effects to docetaxel as a representative of taxoid stabilizers. No evidence of MT bundling in interphase was observed with laulimalide, in spite of the fact that MTs are stabilized at low dose. Cells treated with laulimalide enter mitosis but arrest at prometaphase by generating multiple asters that coalesce into supernumerary poles and interfere with the integrity of the metaphase plate. Cells with a preformed bipolar spindle exist under heightened tension under laulimalide treatment, and chromosomes rapidly shear from the plate, even though the bipolar spindle is well-preserved. Docetaxel generates a similar phenotype for HeLa cells entering mitosis, but when treated at metaphase, cells undergo chromosomal fragmentation and demonstrate reduced centromere dynamics, as expected for a taxoid. Our results suggest that laulimalide represents a new class of molecular probe for investigating MT-mediated events, such as kinetochore-MT interactions, which may reflect the location of the ligand binding site within the interprotofilament groove.
Authors:
Melissa J Bennett; Gordon K Chan; J B Rattner; David C Schriemer
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-08
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-28     Completed Date:  2013-02-04     Revised Date:  2013-08-18    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3045-54     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle Checkpoints
Chromosome Breakage
Chromosomes, Human / drug effects,  metabolism
Dose-Response Relationship, Drug
Fluorescent Antibody Technique / methods
HeLa Cells
Humans
Interphase
Macrolides / pharmacology*
Metaphase
Microtubules / drug effects,  metabolism*
Mitosis / drug effects
Mitotic Spindle Apparatus / drug effects,  metabolism
Molecular Probes / metabolism*,  pharmacology
Taxoids / pharmacology
Time-Lapse Imaging
Chemical
Reg. No./Substance:
0/Macrolides; 0/Molecular Probes; 0/Taxoids; 0/laulimalide; 15H5577CQD/docetaxel
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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