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

Authors
  • Zubovych, Iryna
  • Doundoulakis, Thomas
  • Harran, Patrick G
  • Roth, Michael G
Type
Published Article
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publication Date
Oct 17, 2006
Volume
103
Issue
42
Pages
15523–15528
Identifiers
PMID: 17032754
Source
Medline
License
Unknown

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.

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