Rapid activation of heat shock factor-1 DNA binding by H2O2 and modulation by glutathione in human neuroblastoma and Alzheimer's disease cybrid cells

Gautam N. Bijur, Robert E. Davis, Richard S. Jope

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Because cellular signaling systems are critical mediators of responses to oxidative stress, a condition associated with neurodegenerative disorders, the redox-dependent regulation of heat shock factor-1 (HSF-1) was investigated in human neuroblastoma SH-SY5Y cells. Exposure of cells to 200 μM H2O2 caused a rapid increase in HSF-1 DNA binding that was evident within 10 min, and caused a robust increase that reached levels 8-fold the basal activity. In comparison, the transcription factors, activator protein-1 (AP-1) and early growth response-1 (EGR-1), were activated more slowly and to a lesser extent. Activation of HSF-1 DNA binding activity was associated with a cytosolic to nuclear translocation of HSF-1 protein, and was detected with concentrations of H2O2 of 100 μM and greater. Intracellular glutathione modulated H2O2-induced HSF-1 DNA binding activity, as depletion of glutathione caused HSF-1 to be activated with lower concentrations of H2O2 (25 μM) and supplementation of glutathione blocked HSF-1 activation by 100 to 400 μM H2O2. Alzheimer's disease (AD) and control cybrid cells (SH-SY5Y cells in which the mitochondria were replaced with platelet mitochondria from AD or matched control subjects) were used to test the effects of the chronic oxidative stress caused by the excessive production of reactive oxygen intermediates (ROIs) in AD cybrids on HSF-1 activity. Basal and maximal (induced by H2O2 in glutathione-depleted cells) HSF-1 DNA binding activity were lower in AD than control cybrids, suggesting that the cells had compensated for excessive ROIs. These results indicate that the activation of HSF-1 is highly sensitive to oxidative stress and is regulated by endogenous antioxidant mechanisms. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)69-77
Number of pages9
JournalMolecular Brain Research
Volume71
Issue number1
DOIs
StatePublished - Jul 23 1999
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Cybrid
  • Glutathione
  • Heat shock factor
  • Oxidative stress
  • Reactive oxygen intermediate

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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