Identification of YB-1 as a regulator of PTP1B expression: implications for regulation of insulin and cytokine signaling.
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.
Fukada
Toshiyuki
T
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Tonks
Nicholas K
NK
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D015703:Antigens, CD; D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494201:Il6st protein, rat; D007328:Insulin; D008562:Membrane Glycoproteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C486169:Ybx1 protein, rat; D050822:Cytokine Receptor gp130; D016179:Granulocyte Colony-Stimulating Factor; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516610:Ptpn1 protein, rat