Abstract
Changes in expression of PTP1B, the prototypic protein tyrosine phosphatase, have been associated with various human diseases; however, the mechanisms by which PTP1B expression is regulated have not been defined. We have identified an enhancer sequence within the PTP1B promoter which serves as a binding site for the transcription factor Y box-binding protein-1 (YB-1). Overexpression of YB-1 resulted in increased levels of PTP1B. Furthermore, depletion of YB-1 protein, by expression of a specific antisense construct, led to an approximately 70% decrease in expression of PTP1B, but no change in the level of its closest relative, TC-PTP. Expression of antisense YB-1 resulted in increased sensitivity to insulin and enhanced signaling through the cytokine receptor gp130, which was suppressed by re-expression of PTP1B. Finally, we observed a correlation between the expression of PTP1B and that of YB-1 in cancer cell lines and an animal model of type II diabetes. Our data reveal an important role for YB-1 as a regulator of PTP1B expression, and further highlight PTP1B as a critical regulator of insulin- and cytokine-mediated signal transduction.
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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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Binding Sites
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism*
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Cytokine Receptor gp130
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Cytokines / metabolism*
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DNA-Binding Proteins*
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Diabetes Mellitus, Type 2 / metabolism
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Disease Models, Animal
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Enhancer Elements, Genetic
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Expression Regulation, Enzymologic*
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Genes, Reporter
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Granulocyte Colony-Stimulating Factor / metabolism
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Humans
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Insulin / metabolism*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Molecular Sequence Data
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Muscle, Skeletal / metabolism
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NFI Transcription Factors
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Nuclear Proteins
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / metabolism
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Protein Binding
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases / metabolism*
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Rats
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Rats, Inbred Strains
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology*
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Y-Box-Binding Protein 1
Substances
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Antigens, CD
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CCAAT-Enhancer-Binding Proteins
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Cytokines
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DNA-Binding Proteins
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IL6ST protein, human
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Il6st protein, rat
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Insulin
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Membrane Glycoproteins
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NFI Transcription Factors
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Nuclear Proteins
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Oligonucleotides, Antisense
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Recombinant Fusion Proteins
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Transcription Factors
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Y-Box-Binding Protein 1
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YBX1 protein, human
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Ybx1 protein, rat
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Cytokine Receptor gp130
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Granulocyte Colony-Stimulating Factor
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases
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Ptpn1 protein, rat