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Modulation of Hsf1 activity by novobiocin and geldanamycin

Renaud Conde1, Zachery R Belak, Manoj Nair

  • 1Department of Anatomy and Cell Biology, College of Medicine, 107 Wiggins Rd., University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.

Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire
|November 26, 2009
PubMed

Insights

Hsp90 inhibitors novobiocin and geldanamycin differentially affect heat shock factor 1 (HSF1) activity. Novobiocin impairs HSF1 trimerization, while geldanamycin inhibits HSF1 trimer disassembly.

Area of Science:

  • Molecular Biology
  • Cellular Stress Response
  • Protein Chaperones

Background:

  • Heat shock protein 90 (Hsp90) is a crucial molecular chaperone regulating cellular protein homeostasis.
  • Heat shock factor 1 (HSF1) is a transcription factor that controls the expression of heat shock proteins.
  • Hsp90 modulates HSF1 activity, but the precise mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the effects of Hsp90 inhibitors novobiocin and geldanamycin on HSF1 DNA-binding activity.
  • To elucidate the distinct roles of Hsp90's C-terminal and N-terminal domains in HSF1 regulation.

Main Methods:

  • Utilized the Xenopus oocyte model system.
  • Administered pharmacological inhibitors novobiocin and geldanamycin.
  • Assessed HSF1 DNA-binding and transcriptional activity via dose-dependent treatments and heat shock.
  • Employed immunoprecipitation to analyze Hsp90-HSF1 interactions.

Main Results:

  • Novobiocin treatment decreased HSF1 DNA-binding and transcriptional activity, suggesting its C-terminal ATP-binding inhibition affects HSF1 trimerization.
  • Geldanamycin treatment increased HSF1 trimer stability during heat shock and delayed disassembly, indicating its N-terminal ATPase inhibition affects trimer disassembly.
  • Novobiocin did not disrupt Hsp90-HSF1 complex formation.

Conclusions:

  • Hsp90's C-terminal ATP-binding activity is essential for HSF1 trimerization.
  • Hsp90's N-terminal ATPase and chaperone activities are required for the disassembly of activated HSF1 trimers.
  • Pharmacological inhibition of Hsp90 impacts the heat shock response through distinct mechanisms affecting HSF1 dynamics.

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