Abstract
Signal transducer and activator of transcription 1 (STAT1) mediates gene expression in response to cytokines and growth factors. Activation of STAT1 is achieved through its tyrosine phosphorylation, a process that involves Jak tyrosine kinases. Here we show that STAT1, although phosphorylated on Y701, is unable to localize in the nucleus in the absence of Jak1 or Jak1 kinase activity. In contrast, the nuclear accumulation of STAT1 in Tyk2-deficient cells remains intact. Nuclear presence of tyrosine-phosphorylated STAT1 could be restored in Jak1-deficient cells by leptomycin B, an inhibitor of nuclear export. Amino acids 197 to 205 of STAT1 were found to encode a leucine-rich nuclear export signal (NES). An L-->A mutation within the NES restored nuclear retention of STAT1 in Jak1-deficient cells. Impaired binding of the transcriptional coactivator CBP to tyrosine-phosphorylated STAT1 derived from Jak1-deficient cells offers a model for the intermolecular regulation of the nuclear export sequence.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Biological Transport / drug effects
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CREB-Binding Protein
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Cell Nucleus / metabolism*
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Cells, Cultured / metabolism
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DNA / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Dimerization
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Fatty Acids, Unsaturated / pharmacology
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HeLa Cells / metabolism
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Humans
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Interferons / pharmacology
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Janus Kinase 1
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Models, Molecular
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Neoplasm Proteins / metabolism
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Nuclear Proteins / metabolism*
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Phosphorylation
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Protein Binding
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Protein Conformation
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Protein Processing, Post-Translational
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Protein Sorting Signals / physiology
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology*
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Proteins / genetics
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Proteins / physiology
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Recombinant Fusion Proteins / metabolism
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STAT1 Transcription Factor
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Signal Transduction / physiology*
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TYK2 Kinase
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Trans-Activators / chemistry
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Trans-Activators / metabolism*
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Transcription, Genetic / drug effects
Substances
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DNA-Binding Proteins
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Fatty Acids, Unsaturated
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Neoplasm Proteins
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Nuclear Proteins
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Protein Sorting Signals
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Proteins
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Recombinant Fusion Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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DNA
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Interferons
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CREB-Binding Protein
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CREBBP protein, human
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Janus Kinase 1
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TYK2 Kinase
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TYK2 protein, human
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leptomycin B