Abstract
The heat shock transcription factors (Hsfs) activate the stress-inducible expression of heat shock proteins (Hsps) and other molecular chaperones in response to stress and, therefore, play an essential role in protein disaggregation and protein folding. In humans, missense mutation in the hsf4 gene causes cataract, and mice bearing a targeted disruption of the hsf4 gene exhibit defects in lens fiber cell differentiation and early cataract formation. Here, we show that Hsf4b is a direct target of the mitogen-activated protein (MAP) kinase extracellular signal-related kinase (ERK) and that phosphorylation of Hsf4b by ERK leads to increased ability of Hsf4b to bind DNA. Surprisingly, Hsf4b also interacts with an ERK-specific dual-specificity tyrosine phosphatase named DUSP26 identified from a yeast two-hybrid screen. While activated ERK phosphorylates Hsf4b, DUSP26 controls the activity of ERK, leading to phosphorylation/dephosphorylation of Hsf4b, altering its ability to bind DNA. Therefore, DUSP26 interaction with Hsf4b places this transcription factor within a regulatory circuit in the MAP kinase signaling pathway.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Catalytic Domain
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Cell Line, Tumor
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Cerebellum / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dual-Specificity Phosphatases
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Electrophoretic Mobility Shift Assay
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Gene Deletion
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Gene Expression Regulation*
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Glutathione Transferase / metabolism
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Heat Shock Transcription Factors
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Heterozygote
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Humans
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Immunoblotting
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Immunohistochemistry
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Lung Neoplasms / pathology
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Mice
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Mitogen-Activated Protein Kinase Phosphatases
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Molecular Sequence Data
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Phosphoric Monoester Hydrolases / analysis
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Structure, Tertiary
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Protein Tyrosine Phosphatases / chemistry
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Two-Hybrid System Techniques
Substances
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DNA-Binding Proteins
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HSF4 protein, human
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Heat Shock Transcription Factors
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Hsf4 protein, mouse
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Recombinant Fusion Proteins
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Transcription Factors
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Glutathione Transferase
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Phosphatases
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Phosphoric Monoester Hydrolases
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DUSP26 protein, human
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Dual-Specificity Phosphatases
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Protein Tyrosine Phosphatases