A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance

Iryna Zubovych, Thomas Doundoulakis, Patrick G. Harran, Michael G. Roth

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)15523-15528
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number42
DOIs
StatePublished - Oct 17 2006

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Caenorhabditis elegans
Multiple Drug Resistance
Missense Mutation
Pharmaceutical Preparations
Antimitotic Agents
Nocodazole
Phalloidine
Camptothecin
P-Glycoprotein
Tubulin
Point Mutation
Microtubules
Cell Culture Techniques
Clinical Trials
Drug Therapy
Peptides
Wounds and Injuries
hemiasterlin
prohibitin
Neoplasms

Keywords

  • Antimitotic
  • Hemiasterlin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance. / Zubovych, Iryna; Doundoulakis, Thomas; Harran, Patrick G.; Roth, Michael G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 42, 17.10.2006, p. 15523-15528.

Research output: Contribution to journalArticle

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