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Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. | LitMetric

Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress.

J Biol Chem

Department of Molecular Pharmacology, Mayo Graduate School, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Published: December 2003

AI Article Synopsis

  • DNA damage and replication stress activate the Chk1 signaling pathway, which helps regulate cell cycle progression and stabilize replication forks.* -
  • This study reveals that Chk1 interacts with the molecular chaperone Hsp90, and treatment with the Hsp90 inhibitor 17-AAG leads to destabilization of Chk1, hindering its function.* -
  • The loss of Chk1 due to Hsp90 inhibition increases the sensitivity of tumor cells to gemcitabine, suggesting targeting Hsp90 could enhance cancer treatment effectiveness during replication stress.*

Article Abstract

DNA damage and replication stress activate the Chk1 signaling pathway, which blocks S phase progression, stabilizes stalled replication forks, and participates in G2 arrest. In this study, we show that Chk1 interacts with Hsp90, a molecular chaperone that participates in the folding, assembly, maturation, and stabilization of specific proteins known as clients. Consistent with Chk1 being an Hsp90 client, we also found that Chk1 but not Chk2 is destabilized in cells treated with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG-mediated Chk1 loss blocked the ability of Chk1 to target Cdc25A for proteolytic destruction, demonstrating that the Chk1 signaling pathway was disrupted in the 17-AAG-treated cells. Finally, 17-AAG-mediated disruption of Chk1 activation dramatically sensitized various tumor cells to gemcitabine, an S phase-active chemotherapeutic agent. Collectively, our studies identify Chk1 as a novel Hsp90 client and suggest that pharmacologic inhibition of Hsp90 may sensitize tumor cells to chemotherapeutic agents by disrupting Chk1 function during replication stress.

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Source
http://dx.doi.org/10.1074/jbc.M309054200DOI Listing

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