17-AAG, an Hsp90 inhibitor, causes kinetochore defects: A novel mechanism by which 17-AAG inhibits cell proliferation

Y. Niikura, S. Ohta, K. J. Vandenbeldt, R. Abdulle, B. F. McEwen, K. Kitagawa

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

The Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG), which is currently in clinical trials, is thought to exert antitumor activity by simultaneously targeting several oncogenic signaling pathways. Here we report a novel mechanism by which 17-AAG inhibits cell proliferation, and we provide the first evidence that HSP90 is required for the assembly of kinetochore protein complexes in humans. 17-AAG caused delocalization of several kinetochore proteins including CENP-I and CENP-H but excluding CENP-B and CENP-C. Consistently, 17-AAG induced a mitotic arrest that depends on the spindle checkpoint and induced misalignment of chromosomes and aneuploidy. We found that HSP90 associates with SGT1 (suppressor of G2 allele of skp1; SUGT1) in human cells and that depletion of SGT1 sensitizes HeLa cells to 17-AAG. Overexpression of SGT1 restored the localization of specific kinetochore proteins and chromosome alignment in cells treated with 17-AAG. Biochemical and genetic results suggest that HSP90, through its interaction with SGT1 (SUGT1), is required for kinetochore assembly. Furthermore, time-course experiments revealed that transient treatment with 17-AAG between late S and G2/M phases causes substantial delocalization of CENP-H and CENP-I, a finding that strongly suggests that HSP90 participates in kinetochore assembly in a cell cycle-dependent manner.

Original languageEnglish (US)
Pages (from-to)4133-4146
Number of pages14
JournalOncogene
Volume25
Issue number30
DOIs
StatePublished - Jul 13 2006
Externally publishedYes

Keywords

  • 17-AAG
  • Centromere
  • HSP90
  • Kinetochore
  • SGT1 (SUGT1)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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