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Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15523-8. Epub 2006 Oct 10.

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

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  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.

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.

PMID:
17032754
[PubMed - indexed for MEDLINE]
PMCID:
PMC1622856
Free PMC Article
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