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  1. 学位論文
  2. 博士論文(医学)
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Liganded T3 receptor β2 inhibits the positive feedback autoregulation of the gene for GATA2, a transcription factor critical for thyrotropin production

http://hdl.handle.net/10271/00004209
http://hdl.handle.net/10271/00004209
766285f2-df3c-4bb6-b409-41a24a5639a0
名前 / ファイル ライセンス アクション
DT_ron585ronbun.pdf 論文本文 (2.6 MB)
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Item type 学位論文 / Thesis or Dissertation(1)
公開日 2022-11-28
タイトル
タイトル Liganded T3 receptor β2 inhibits the positive feedback autoregulation of the gene for GATA2, a transcription factor critical for thyrotropin production
言語 en
言語
言語 eng
資源タイプ
資源タイプ識別子 http://purl.org/coar/resource_type/c_db06
資源タイプ doctoral thesis
アクセス権
アクセス権 open access
アクセス権URI http://purl.org/coar/access_right/c_abf2
その他のタイトル
その他のタイトル T3結合受容体β2はサイロトロピン産生に必須な転写因子GATA2の遺伝子発現における自動制御/正のフィードバック機構を負に調節する
その他のタイトル
その他のタイトル T3 inhibits GATA2 gene autoregulation
著者 平原, 直子

× 平原, 直子

ja 平原, 直子

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書誌情報 en : PLOS ONE

巻 15, 号 1, p. e0227646, 発行日 2020-01-15
出版者
出版者 PLOS (Public Library of Science)
言語 en
権利
言語 en
権利情報 Copyright 2020 Hirahara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
抄録
内容記述タイプ Abstract
内容記述 The serum concentration of thyrotropin (thyroid stimulating hormone, TSH) is drastically reduced by small increase in the levels of thyroid hormones (T3 and its prohormone, T4); however, the mechanism underlying this relationship is unknown. TSH consists of the chorionic gonadotropin α (CGA) and the β chain (TSHβ). The expression of both peptides is induced by the transcription factor GATA2, a determinant of the thyrotroph and gonadotroph differentiation in the pituitary. We previously reported that the liganded T3 receptor (TR) inhibits transactivation activity of GATA2 via a tethering mechanism and proposed that this mechanism, but not binding of TR with a negative T3-responsive element, is the basis for the T3-dependent inhibition of the TSHβ and CGA genes. Multiple GATA-responsive elements (GATA-REs) also exist within the GATA2 gene itself and mediate the positive feedback autoregulation of this gene. To elucidate the effect of T3 on this non-linear regulation, we fused the GATA-REs at -3.9kb or +9.5kb of the GATA2 gene with the chloramphenicol acetyltransferase reporter gene harbored in its 1S-promoter. These constructs were co-transfected with the expression plasmids for GATA2 and the pituitary specific TR, TRβ2, into kidney-derived CV1 cells. We found that liganded TRβ2 represses the GATA2-induced transactivation of these reporter genes. Multi-dimensional input function theory revealed that liganded TRβ2 functions as a classical transcriptional repressor. Then, we investigated the effect of T3 on the endogenous expression of GATA2 protein and mRNA in the gonadotroph-derived LβT2 cells. In this cell line, T3 reduced GATA2 protein independently of the ubiquitin proteasome system. GATA2 mRNA was drastically suppressed by T3, the concentration of which corresponds to moderate hypothyroidism and euthyroidism. These results suggest that liganded TRβ2 inhibits the positive feedback autoregulation of the GATA2 gene; moreover this mechanism plays an important role in the potent reduction of TSH production by T3.
言語 en
学位名
学位名 博士(医学)
学位の区分
内容記述 doctoral
学位の分野
内容記述 医学系研究科
学位授与機関
学位授与機関識別子Scheme kakenhi
学位授与機関識別子 13802
学位授与機関名 浜松医科大学
学位授与年月日
学位授与年月日 2021-12-17
学位授与番号
学位授与番号 乙第585号
EISSN
収録物識別子タイプ EISSN
収録物識別子 1932-6203
PubMed番号
識別子タイプ PMID
関連識別子 31940421
出版社DOI
識別子タイプ DOI
関連識別子 https://doi.org/10.1371/journal.pone.0227646
著者版フラグ
出版タイプ VoR
出版タイプResource http://purl.org/coar/version/c_970fb48d4fbd8a85
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