A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance.
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.
Zubovych
Iryna
I
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
Doundoulakis
Thomas
T
Harran
Patrick G
PG
Roth
Michael G
MG
D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins; D002460:Cell Line; D018432:Drug Resistance, Multiple / Q000502:physiology; D005816:Genetic Complementation Test; D006801:Humans; D015394:Molecular Structure; D020125:Mutation, Missense; D015739:Nocodazole / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010590:Phalloidine / Q000494:pharmacology; D000091402:Prohibitins; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D009842:Oligopeptides; C000717328:PHB protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D020033:Protein Isoforms; D012097:Repressor Proteins; D014404:Tubulin; D050257:Tubulin Modulators; C000717338:prohibitin 2, C elegans; D010590:Phalloidine; C467070:hemiasterlin; D015739:Nocodazole