A Missense Mutation in Caenorhabditis Elegans Prohibitin 2 Confers an Atypical Multidrug Resistance.
From: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
Proceedings of the National Academy of Sciences of the United States of America
- Publish Date: Oct 2006
- ISSN: 0027-8424
- Volume: 103
- Issue: 42
- Pages: 15523-8
- Medium: Print
- Language: English
- Citation (JAMA): Zubovych Iryna, Doundoulakis Thomas, Harran Patrick G, et al. A Missense Mutation in Caenorhabditis Elegans Prohibitin 2 Confers an Atypical Multidrug Resistance.. Proc. Natl. Acad. Sci. U.S.A. Oct 2006;103:15523-8
Abstract
Hemiasterlin is a potent antimitotic peptide that interferes with microtubule dynamics at picomolar concentrations in cell culture. The molecule largely eludes P glycoprotein-mediated drug efflux, and an analog is currently being evaluated in clinical trials as cancer chemotherapy. From a nonclonal genetic screen in Caenorhabditis elegans we isolated eight independent mutants resistant to a synthetic hemiasterlin analog. In one recessive mutant, phb-2(ad2154), a point mutation in prohibitin 2 (E130K) protects worms from drug-induced injury. Data indicate that direct binding of hemiasterlin to prohibitin 2 is unlikely. In fact, C. elegans phb-2(ad2154) was also found to be resistant to numerous other drugs that bind tubulin and to camptothecin, yet this mutant was sensitive to nocodazole and phalloidin. Thus, prohibitin 2 is implicated in a previously uncharacterized pathway of multidrug resistance.
Mesh Headings (Keywords): Animals, Antinematodal Agents, Caenorhabditis elegans, Cell Line, Drug Resistance, Multiple, Genetic Complementation Test, Humans, Molecular Structure, Mutation, Missense, Nocodazole, Oligopeptides, Phalloidine, Protein Isoforms, Repressor Proteins, Tubulin, Tubulin Modulators
Check for Full Text / PubMed Unique Identifier (PMID): 17032754
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