title: Protein-disulfide isomerase regulates the thyroid hormone receptor-mediated gene expression via redox factor-1 through thiol reduction-oxidation.
abstract: Protein-disulfide isomerase (PDI) is a dithiol/disulfide oxidoreductase that regulates the redox state of proteins. We previously found that overexpression of PDI in rat pituitary tumor (GH3) cells suppresses 3,3',5-triiodothyronine (T(3))-stimulated growth hormone (GH) expression, suggesting the contribution of PDI to the T(3)-mediated gene expression via thyroid hormone receptor (TR). In the present study, we have clarified the mechanism of regulation by which TR function is regulated by PDI. Overexpression of wild-type but not redox-inactive mutant PDI suppressed the T(3)-induced GH expression, suggesting that the redox activity of PDI contributes to the suppression of GH. We considered that PDI regulates the redox state of the TR and focused on redox factor-1 (Ref-1) as a mediator of the redox regulation of TR by PDI. Interaction between Ref-1 and TRβ1 was detected. Overexpression of wild-type but not C64S Ref-1 facilitated the GH expression, suggesting that redox activity of Cys-64 in Ref-1 is involved in the TR-mediated gene expression. Moreover, PDI interacted with Ref-1 and changed the redox state of Ref-1, suggesting that PDI controls the redox state of Ref-1. Our studies suggested that Ref-1 contributes to TR-mediated gene expression and that the redox state of Ref-1 is regulated by PDI. Redox regulation of PDI via Ref-1 is a new aspect of PDI function.
authors.affiliation: Research Center for Environmental Bioscience and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Hyogo, Sanda 669-1337, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Susumu
authors.initials: S
authors.lastname: Imaoka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008156:Luciferases; D010084:Oxidation-Reduction; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D013006:Growth Hormone; D008156:Luciferases; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D019704:Protein Disulfide-Isomerases