B型肝炎ウイルスX蛋白の機能

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Author: 村上, 清史ほか

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Publication date: 2008-05-26

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Note (General)：: 金沢大学がん研究所HBV X蛋白(HBx)はRNA polymerase subunit 5(RPB5)及びTFIIBと相互作用し、転写のcoactivatorとして機能することをin vivo及びin vitro転写系で報告した。HBxの転写修飾の分子機構の解明とHBxのHBVウイルス増殖への影響...

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https://kaken.nii.ac.jp/search/?qm=90019878

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https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-12213050/122130502004kenkyu_seika_hokoku_gaiyo/

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Material Type: 文書・図像類
Title: B型肝炎ウイルスX蛋白の機能
Author/Editor: 村上, 清史
Murakami, Seishi
Author Heading: 村上, 清史
Murakami, Seishi
Publication Date: 2008-05-26
Publication Date (W3CDTF): 2008-05-26
Alternative Title: Function of Hepatitis B Virus X protein
Periodical title: 平成16(2004)年度科学研究費補助金特定領域研究研究成果報告書概要 = 2004 Fiscal Year Final Research Report Summary
No. or year of volume/issue: 2000 – 2004
Volume: 2000 – 2004
Pages: 4p.-
Text Language Code: jpn
Subject Heading: HBV X蛋白
RNAポリメラーゼ
RPB5
RMP
HBVレプリコン
転写修飾
テロメラーゼ
HBv X protein
RNA polymerase
HBV replicon
Transcriptional modulation
Telomerase
Target Audience: 一般
Note (General): 金沢大学がん研究所
HBV X蛋白(HBx)はRNA polymerase subunit 5(RPB5)及びTFIIBと相互作用し、転写のcoactivatorとして機能することをin vivo及びin vitro転写系で報告した。HBxの転写修飾の分子機構の解明とHBxのHBVウイルス増殖への影響と宿主細胞への影響を評価を検討した。1.RPB5の中央部と基本転写因子TFIIFサブユニットRAP30の結合が、Pol IIとTFIIFの会合に必須で、RAP30の中央部の2残基がこの結合に関与していた。置換、変異を用いHBxの結合に必須な6残基と、TFIIFサブユニットRAP30との結合に必須な6残基を特定し、その内4残基が共通であった(投稿中)。RPB5のDNA結合能にもこの4残基が必須または重要であるから、RPB5のDNA結合能がRPB5の転写修飾の標的である可能性が示された。2.HBxに拮抗するRMP/URIの相互作用パートナーとしてcorepressorであるDMAP1を同定した。また、RMP/URIの細胞内局在を検討した結果、RMP/URIは細胞質と核内とで異なった機能を持つ制御蛋白と考えられた。3.野生型及びHBVレプリコンに外来性HBxを共存させHBV複製を検討した。HBxのcoactivationドメイン内の2つの不連続な領域がHBV複製促進及びHBV DNA複製の鋳型となるpregenomic (pg) RNAの合成に必要であった。HBxのcoactivation能がpgRNA合成の促進に必要で、この効果によりHBV DNA複製が元進されると推定された。4.HBxのヒト初代細胞の不死化と、ヒト不死化細胞の形質転換へ及ぼす効果を、野生型及び各種HBx発現レトルウイルスを用いて解析した。HBx及びHBxのcoactivationドメインは、不死化効率には影響を与えないが、形質転換率を促進する結果を得た。
For better understanding molecular mechanism of transcriptional modulation by HBV X protein (HBx), we studied structure and function of RNA polymerase subunit 5 (RPB5) as a nuclear target of HBx, and contribution of HBx on immortalization and/or transformation process of human cells. In addition, subcellular localization and nuclear function of RMP which is a functional antagonist of HBx. The followings are main results of the project in this fiscal year.1) By analyzing clustered alanine substitution mutant (Cm) and point mutant (Pm) libraries of the middle part of RPB5, we pinpointed 6 resideus critical for HBx-binding and 6 residues for TFIIF subunit RAP30-binding.Among them, 4 residues・F76, 1104, T111 and S113, are critical both for the bindings. The former two residues are not solvent exposed and probably contributing to the structural integrity. T111 and S113 are exposed and is in near position to DNA in light of the Pol II crystal models. The 4 residues are also critical or important for DNA-binding ability of RPB5 (in preparation). Taken together, DNA-binding ability of RPB5 may be the target of HBx and RAP30.2) Using the Cm library of HBx, we addressed the critical region(s) of HBx for augmentation ability on HBV replication in a HBV replicon system. which is defective in X-ORF. Two discontinuous regions in the coactivation domain of HBx are indispensable for the augmentation effect on HBV replication. In the same experiment, the same regions were required not only for increase in HBV DNA but also for increase in pregenomic (pg) RNA. The same regions were also critical for the coactivation function of HBx, suggesting that HBx coactivates pgRNA synthesis that resulted in increase in HBV DNA synthesis.3) Recently it was found that RMP/URI, a functional antagonist of HBx, is localized with RPB5 in cytoplasm. Subcellular localization of RMP/URI can be modulated in the presence of DMAP1 and nuclear RMP/URI acts as a corepressor. From these results, RMP/URI is a regulatory protein in cytoplasm as well as nucleus.4) We addressed whether HBx acts positively in immortalization and/or transformation process of human cells. In our preliminary results, immortalization of human primary cells is barely affected by HBx, but transformation frequency of immortalized human cells seems to be augmented by HBx in the presence of activated oncogenes. This facilitating role of HBx requires the coactivation domain of HBx.
研究課題/領域番号:13555218, 研究期間(年度):2001-2010
出典：研究課題「B型肝炎ウイルスX蛋白の機能」課題番号12213050（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-12213050/122130502004kenkyu_seika_hokoku_gaiyo/）を加工して作成
DOI: 10.24517/00066729
Access Restrictions: 限定公開
Related Material: https://kaken.nii.ac.jp/search/?qm=90019878
https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-12213050/
https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-12213050/122130502004kenkyu_seika_hokoku_gaiyo/
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA