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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antinematodal Agents / pharmacology*
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Caenorhabditis elegans / drug effects*
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Caenorhabditis elegans / genetics*
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Caenorhabditis elegans / physiology
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Caenorhabditis elegans Proteins
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Cell Line
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Drug Resistance, Multiple / physiology
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Genetic Complementation Test
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Humans
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Molecular Structure
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Mutation, Missense*
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Nocodazole / pharmacology
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Oligopeptides / chemistry
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Oligopeptides / pharmacology*
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Phalloidine / pharmacology
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Prohibitins
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism
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Tubulin / metabolism
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Tubulin Modulators / chemistry
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Tubulin Modulators / pharmacology*
Substances
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Antinematodal Agents
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Caenorhabditis elegans Proteins
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Oligopeptides
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PHB protein, human
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PHB2 protein, human
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Prohibitins
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Protein Isoforms
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Repressor Proteins
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Tubulin
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Tubulin Modulators
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prohibitin 2, C elegans
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Phalloidine
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hemiasterlin
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Nocodazole