Interactions between extracellular signal-regulated protein kinase 1, 14-3-3epsilon, and heat shock factor 1 during stress

J Biol Chem. 2004 Nov 19;279(47):49460-9. doi: 10.1074/jbc.M406059200. Epub 2004 Sep 10.


Cytoprotection during the heat shock response is a complex phenomenon involving multiple inducible mechanisms. We have examined the interaction of two key molecular components in the response, heat shock transcription factor 1 (HSF1) and extracellular signal regulated protein kinase (ERK). Whereas both HSF1 and ERK are required to protect cells against apoptosis, ERK activation is paradoxically antagonistic to trans-activation of hsp promoters by HSF1 and HSP accumulation during heat shock. We have found that the two pathways interact directly and that heat shock causes the physical association of ERK1 with HSF1, an interaction that promotes the kinase activity of ERK in heat-shocked cells. ERK activation results in the recruitment of the phosphoserine binding protein 14-3-3epsilon in a manner dependent on previous HSF1 phosphorylation by ERK. The effects of 14-3-3epsilon binding on HSF1 were complex, however, depending on extracellular conditions, in that HSF1-14-3-3 binding at 37 degrees C led to the cytoplasmic sequestration and repression of HSF1, whereas heat shock overrode these effects and caused quantitative nuclear localization of HSF1. Although the effects of 14-3-3epsilon binding to HSF1 were overridden acutely by stress, during recovery from heat shock, 14-3-3epsilon association again led to enhanced cytoplasmic localization of HSF1, implicating a role for ERK/14-3-3epsilon in HSF1 deactivation in recovering cells. Association of HSF1 with ERK and 14-3-3epsilon during heat shock may thus modulate the amplitude of the response and lead to efficient termination of HSP expression on resumption of growth conditions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Animals
  • Apoptosis
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / metabolism*
  • Glutathione Transferase / metabolism
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Hot Temperature
  • Humans
  • Kinetics
  • MAP Kinase Signaling System
  • Mice
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • NIH 3T3 Cells
  • Phosphorylation
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Biosynthesis
  • Ribosomal Protein S6 Kinases / metabolism
  • Temperature
  • Time Factors
  • Transcription Factors
  • Transcriptional Activation
  • Transfection


  • 14-3-3 Proteins
  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Transcription Factors
  • YWHAE protein, human
  • Green Fluorescent Proteins
  • Glutathione Transferase
  • Ribosomal Protein S6 Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3