JP5227757B2 - 新規置換突然変異体受容体および核受容体−ベースの誘導性遺伝子発現システムにおけるその使用 - Google Patents
新規置換突然変異体受容体および核受容体−ベースの誘導性遺伝子発現システムにおけるその使用 Download PDFInfo
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Description
本開示においては、多数の用語および略語が用いられる。以下の定義が設けられ、それは、本発明の範囲および実施を理解するのに助けとなるはずである。
出願人らは、エクジソン受容体−ベースの誘導性遺伝子発現システムにおいてリガンド感受性および誘導の大きさに影響するグループH核受容体リガンド結合ドメインへのリガンド結合に関与するアミノ酸残基をここに同定した。出願人らは、ここに、これらの臨界的残基における置換突然変異を含むグループH核受容体の構築(ここでは「置換突然変異体」という)、およびこれらの置換突然変異体核受容体が遺伝子発現を変調する方法で有用である証明を記載する。本明細書に提示するように、出願人らの新規な置換突然変異体核受容体および核受容体−ベースの誘導性遺伝子発現システムにおけるそれらの使用は、原核生物および真核生物宿主細胞双方において、リガンド感受性およびトランス活性化の大きさが、適用に応じて、所望により選択することができる改良された誘導性遺伝子発現システムを提供する。
本発明の新規な核受容体−ベースの誘導性遺伝子発現システムは、宿主細胞で発現させることができる少なくとも1つの遺伝子発現カセットを含み、ここに、該遺伝子発現カセットは置換突然変異を含むグループH核受容体リガンド結合ドメインを含むポリペプチドをコードするポリヌクレオチドを含む。かくして、出願人らの発明は、本発明の遺伝子発現システムで用いる新規な遺伝子発現カセットも提供する。
本発明の新規な核受容体−ベースの誘導性遺伝子発現システムは、置換突然変異を含むグループH核受容体リガンド結合ドメインをコードするポリヌクレオチドを含む少なくとも1つの遺伝子発現カセットを含む。これらの遺伝子発現カセット、それが含むポリヌクレオチドおよびそれがコードするポリペプチドは、宿主細胞内で遺伝子の発現を変調するための核受容体−ベースの遺伝子発現システムの構成要素として有用である。
本発明の新規な核受容体−ベースの誘導性遺伝子発現システムは、置換突然変異を含むグループH核受容体リガンド結合ドメインを含むポリペプチドをコードするポリヌクレオチドを含む少なくとも1つの遺伝子発現カセットを含む。かくして、本発明は、本発明による置換突然変異を含むグループH核受容体リガンド結合ドメインを含む単離されたポリペプチドも提供する。
また、出願人らの発明は、本発明による遺伝子発現変調システムを用いて宿主細胞中で遺伝子発現を変調する方法に関する。具体的には、出願人らの発明は、a)本発明の遺伝子発現変調システムを宿主細胞に導入し;次いで、b)宿主細胞にリガンドを導入することを含み、変調すべき遺伝子は、i)遺伝子発現システムのDNA結合ドメインによって認識されるドメインを含む応答エレメント;ii)遺伝子発現システムのトランス活性化ドメインによって活性化されるプロモーター;およびiii)その発現を変調すべき遺伝子を含む遺伝子発現カセットの構成要素であり、それにより、リガンドの宿主細胞への導入に際して遺伝子の発現が変調される工程を含む、宿主細胞中で遺伝子の発現を変調する方法を提供する。
R1はH、Me、Et、i−Pr、F、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CH2OMe、CH2CN、CN、C0CH、1−プロピニル、2−プロピニル、ビニル、OH、OMe、OEt、シクロプロピル、CF2CF3、CH=CHCN、アリル、アジド、SCNまたはSCHF2であり;
R2はH、Me、Et、n−Pr、i−Pr、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CH2OMe、CH2CN、CN、C0CH、1−プロピニル、2−プロピニル、ビニル、Ac、F、Cl、OH、OMe、OEt、O−n−Pr、OAc、NMe2、NEt2、SMe、SEt、SOCF3、OCF2CF2H、COEt、シクロプロピル、CF2CF3、CH=CHCN、アリル、アジド、OCF3、OCHF2、O−i−Pr、SCN、SCHF2、SOMe、NH−CNであるか、またはR3、ならびにR2およびR3が結合したフェニル炭素と一緒になって、エチレンジオキシ、フェニル炭素に隣接した酸素を持つジヒドロフリル環、もしくはフェニル炭素に隣接する酸素を持つジヒドロピリル環を形成し;
R3はH、Etであるか、またはR2、ならびにR2およびR3が結合したフェニル炭素と一緒になって、エチレンジオキシ、フェニル炭素に隣接した酸素を持つジヒドロフリル環、もしくはフェニル炭素に隣接した酸素を持つジヒドロピリル環を形成し;
R4、R5およびR6は独立してH、Me、Et、F、Cl、Br、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CN、C0CH、1−プロピニル、2−プロピニル、ビニル、OMe、OEt、SMeまたはSEtである。)
の化合物である。
前記したように、本発明の遺伝子発現変調システムを用いて、宿主細胞において遺伝子発現を変調することができる。トランスジェニック宿主細胞における発現は、注目する種々の遺伝子の発現で有用であり得る。出願人らの発明は、原核生物および真核生物宿主細胞における遺伝子発現の変調を提供する。トランスジェニック宿主細胞における発現は、限定されるものではないが、ワクチンとして植物で生産される抗原、アルファ−アミラーゼ、フィターゼ、グルカン、キシラーゼおよびキシラナーゼのような酵素、昆虫、線虫、真菌類、細菌、ウィルスおよび無生物ストレス、抗原、栄養補給食品、医薬、ビタミンに対する抵抗性についての遺伝子、アミノ酸含有量、除草剤抵抗性、寒気、日照りおよび熱許容性、産業製品、油、蛋白質、炭水化物、抗酸化剤、雄性不稔植物、花、燃料、他の出力特性、治療ポリペプチド、経路中間体を修飾する遺伝子を含めた注目する種々のポリペプチドの発現に有用であり;宿主を用いて以前には可能で無かった新しい産物の合成のための宿主に既に存在する経路の変調;細胞ベースのアッセイ;機能的ゲノミクスアッセイ、バイオ治療蛋白質生産、プロテオミクスアッセイ等の変調に有用である。加えて、遺伝子産物は、宿主のより高い増殖量を付与するのに、あるいは利用すべき別の増殖様式を可能とするのに有用であろう。
本発明の出願人らの方法の1つの有用な測定は、RNA、好ましくはmRNA種の同一性および存在量を含めた細胞の転写状態の測定である。そのような測定は、いくつかの現存する遺伝子発現技術のうちのいずれかによってcDNAの存在量を測定することによって簡便に行われる。
また、本発明は、核受容体リガンド結合ドメインを候補分子と接触させ、リガンドの存在下でレポーター遺伝子の活性を測定することによる、細胞において置換突然変異を含む核受容体リガンド結合ドメインのトランス活性化を誘導または抑制する化合物につきスクリーニングする方法に関する。候補化合物は、核受容体リガンド結合ドメインのアゴニストまたはアンタゴニストであり得る。好ましい実施形態においては、核受容体リガンド結合ドメインは細胞中のポリヌクレオチドから発現され、トランス活性化活性(すなわち、レポーター遺伝子の発現または抑制)または化合物の結合活性が測定される。
出願人らは、CfEcR相同性モデルを開発し、公開されたChironomous tetansエクジソン受容体(「CtEcR」)相同性モデル(Wurtzら、2000)と一緒にこの相同性モデルを用いて、ステロイドおよび非−ステロイドへの結合に関与する臨界的残基を同定した。合成非−ステロイド、ジアシルヒドラジンは、高い親和性をもって鱗翅目EcRに結合し、これらの昆虫において早めの不完全な脱皮を誘導することが示されており(Wingら、1988)、これらの化合物のうち数個は現在殺虫剤として市販されている。EcRのリガンド結合キャビティは、20Eといったエクジステロイドの長い骨格構造に適合するように進化している。該ジアシルヒドラジンはステロイドと比較してコンパクトな構造を有し、EcR結合ポケットの底部のみを占有する。これは、ステロイドと接触するが、ジアシルヒドラジンといった非−ステロイドとは接触しない結合ポケットの頂部に数個の臨界的残基を残す。出願人らは、ステロイドおよび/または非−ステロイドと接触する残基の置換突然変異を作成し、リガンド結合に対する突然変異の効果を測定した。出願人らは、ここに、それらの残基の数個における置換突然変異を記載し、それらの結合およびトランス活性化特徴に基づいて置換突然変異体受容体のいくつかのクラスを同定した。出願人らの新規な置換突然変異した核受容体ポリヌクレオチドおよびポリペプチドは、遺伝子治療、宿主細胞における注目する蛋白質の発現、トランスジェニック生物の生産、および細胞−ベースのアッセイを含めた種々の適用のための核受容体−ベースの誘導性遺伝子変調システムで有用である。
ここに用いる標準的な組換えDNAおよび分子クローニング技術は当該分野でよく知られており、Sambrook,J.、Fritsch,E.F.およびManiatis,T.、Molecular Cloning:A Laboratory Manual:Cold Spring Harbor Laboratory Press:Cold Spring Harbor、N.Y.(1989)(Maniatis)によって、およびT.J.Silhavy、M.L.BennanおよびL.W.Enquist、Experiments with Gene Fusions、Cold Spring Harbor Laboratory、Cold Spring Harbor、N.Y.(1984)によって、およびAusubel,F.M.ら、Current Protocols in Molecular Biology、Greene Publishing Assoc.およびWiley−Interscience(1987)によって記載されている。
EcRリガンド結合を修飾する努力において、分子モデリング分析に基づいてリガンド結合に対して重要であると予測されたEcRリガンド結合ドメイン内の残基を、生物の3つの異なるクラスからのEcRにおいて突然変異させた。表1−3は、各々、ステロイドおよび非−ステロイド結合の修飾につき突然変異させ、調べたCfEcR(鱗翅目EcR)、DmEcR(双翅目EcR)およびAmaEcR(節足動物EcR)のリガンド結合ドメイン内のアミノ酸残基を示す。
出願人らは、ステロイドおよび非−ステロイドリガンド結合アッセイにおいてA110P突然変異体CfEcR受容体をテストして、ステロイド結合が排除されたことを確認した。簡単に述べれば、イン・ビトロリガンド結合アッセイ(LBA)を用いてPonA結合活性を測定した。3H−PonA(200Ci/ミリモル)を用いてステロイドリガンド結合アッセイ(LBA)を行った。イン・ビトロで翻訳されたGal4/野生型またはA110P突然変異体CfEcR−DEFおよび細菌で発現されたGST−CfUSP−A/BCDEFを該アッセイで用いた。該アッセイは、T緩衝液[製造業者の指示(Boehringer Mannheim)に従って用いたComplete(商標)プロテアーゼ阻害剤カクテルを含む90mMトリスpH8.0、10μMのDTT]の存在下において、8μLのGal4/野生型またはA110P突然変異体CfEcR−DEF、2.5μLのGST−CfUSP−A/BCDEF、1μLの3H−PonAおよびコンペティターとしての2μLの未標識(「コールド」)PonAで行った。該反応は室温にて1時間行い、続いてデキストラン−被覆チャコール(charcoal)(Sigma)を添加した。混合物を7000×gにて10分間遠心し、上清中の3H−PonAの量を測定した。該反応は三連で行った。また、全長野生型EcRまたはそのA110P突然変異体をイン・ビトロで翻訳し、製造業者の指示に従ってTNTシステム(Promega)を用いて転写し、コンペティターとしてのコールド20Eまたは非−ステロイド(RH2485およびGS(商標)−E)を用いて、3H−RH2485を用いてイン・ビトロリガンド結合アッセイでテストした。加えて、標準的な方法に従うSDS−PAGE(Maniatis、1989)を用い、5μLのイン・ビトロ翻訳を翻訳効率につきアッセイした。野生型およびA110P突然変異体CfEcR−DEF受容体の双方についてのリガンド結合結果を計算し、それを図1に示す。
ステロイド活性の喪失がトランケートされたCfEcR−DEF受容体またはGAL4融合蛋白質のアーティファクトによるであろう可能性を排除するために、出願人らはA110P突然変異を全長(FL)CfEcR(CfEcR−A/BCDEF)に導入し、実施例1.4に記載したようにそれをGAL4 DNA結合ドメインに融合させ、VP16/LmUSP−EF、ならびにエクジソン応答エレメントの6コピー(6×EcRE)および合成TATAAに作動可能に連結したルシフェラーゼレポーター遺伝子発現を含むpFREcRE Lucと組み合わせた、全長野生型CfEcR(実施例1.3)と比較して、上記実施例2に記載したように24−ウェルプレートにてNIH3T3細胞中でそれをアッセイした。トランスフェクトされた細胞を0.25または10μMのPonAまたはGS(商標)−Eの存在下で増殖させ、リガンド添加から40時間後に、レポーター活性を測定した。細胞を回収し、抽出物をルシフェラーゼ活性につきアッセイした。結果を図2に示す。棒線の頂部の数は、DMSOレベルに対する増加倍数を示す。
哺乳動物細胞においては、EcRの天然リガンドである20−ヒドロキシエクジソン(20E)はCfEcR−ベースの遺伝子発現システムを通じてトランス活性化を誘導しない。A110P突然変異体が20Eに応答できるか否かを決定するために、出願人らは昆虫L57細胞(EcRアイソフォームB、それからA110P突然変異体が由来するCfEcRアイソフォームBのDrosophila melanogaster EcRアイソフォームホモログを欠くDrosophila melanogaster細胞系、ただし、L57細胞は依然としてEcRアイソフォームAを含有する)にてのEcRE−駆動レポーターアッセイでこのA110P突然変異体−ベースの遺伝子発現システムをテストした。該突然変異をVP16/CfEcR−CDEF融合蛋白質に導入し、バキュロウイルスIE1プロモーターに作動可能に連結させ、24−ウェルプレート中で、6×エクジソン応答エレメント(「6×EcRE」;pMK43.2構築体はStanford UniversityのMichael Koelleから得た)の制御下にあるpMK43.2β−ガラクトシダーゼレポーター遺伝子と共にIE1VP16CfEcRCDEF(実施例1.5)またはそのA110P突然変異体バージョンDNA(実施例1.6)でL57細胞をトランスフェクトした。40時間の0、1、10、100または1000nMの20EまたはGS(商標)−Eでのトランスフェクト細胞の処理後に、A110P突然変異体−ベースの遺伝子発現システムトランス活性化についてのレポーター活性を測定した。細胞を回収し、抽出物をβ−ガラクトシダーゼ(β−GAL)およびルシフェラーゼ活性につきアッセイした。β−ガラクトシダーゼは、製造業者の指示に従い、TROPIXからのGalacto−Star(商標)アッセイキットを用いて測定した。棒線の頂部の数はDMSOレベルに対する増加倍数を示す。結果を図3に示す。
4つの突然変異:A110S、A110P、A110LおよびA110Mを得た。これらの4つの突然変異体および野生型受容体をNIH3T3細胞でアッセイした。4つの突然変異体または野生型CfEcR−DEF受容体、VP16LmUSP−EFおよびpFRLUCの各々のGAL4融合物をNIH3T3細胞にトランスフェクトし、0、0.04 、0.2、1、5または25μMのPonA、MurA、N−(2−エチル−3−メトキシベンゾイル)−N’−(3,5−ジメチルベンゾイル)−N’−tert−ブチルヒドラジン(GS(商標)−E非−ステロイドリガンド)、またはN’−tert−ブチル−N’−(3,5−ジメチルベンゾイル)−3,4−(1,2−エチレンジオキシ)−2−メチルベンゾヒドラジド(RH−125020)の存在下にて細胞を48時間増殖させ、レポーター活性を測定した。図4に示すように、野生型エクジソンレポーターは、ステロイドおよび非−ステロイド双方の存在下にてレポーター活性を示した。しかしながら、全ての突然変異体受容体は非−ステロイドリガンドの存在下でのみレポーター活性を示したが、ステロイドリガンドの存在下では示さなかった。A110P突然変異体は野生型受容体と比較して同様の非−ステロイド活性を呈したが、A110S、A110LおよびA110M突然変異体は2つの最低濃度においてより低い感受性を示し、検出可能なトランス活性化は示さなかった。これらの結果は、A110置換突然変異体EcRリガンド結合ドメインがステロイドに対する有意に低下した応答によって特徴付けられるが、依然として非−ステロイドに対して応答性であることを確認する。
本実施例は、前記にて同定したCfEcRリガンド結合ドメイン置換突然変異体に類似するAmaEcRリガンド結合ドメイン内のアミノ酸残基においてAmblyomma americanum EcR(AmaEcR)内への置換突然変異の導入を記載する。具体的には、各々、CfEcRの配列番号:1のアミノ酸残基96および110に対応するAmaEcRの配列番号:3のアミノ酸残基91および105において置換突然変異を導入した。
Claims (43)
- (a)i)トランス活性化ドメイン;
ii)その発現を変調すべき遺伝子と関連した応答エレメントを認識するDNA−結合ドメイン;および
iii)置換突然変異を含むグループH核受容体リガンド結合ドメイン
を含むポリペプチドをコードするポリヌクレオチド;ならびに
(b)i)DNA結合ドメインによって認識される応答エレメント;
ii)トランス活性化ドメインによって活性化されるプロモーター;および
iii)その発現が変調されるべき遺伝子
を含むポリヌクレオチド
を含み、
該グループH核受容体リガンド結合ドメインはコドン突然変異を含むポリヌクレオチドによりコードされ、該コドン突然変異は、
a)配列番号:1のアミノ酸残基107、
b)配列番号:1のアミノ酸残基175、
c)配列番号:1のアミノ酸残基107および175、
d)配列番号:1のアミノ酸残基107および127、
e)配列番号:1のアミノ酸残基127および175、
f)配列番号:1のアミノ酸残基107、127、および175、または
g)配列番号:1のアミノ酸残基52、107および175
においてアミノ酸残基の置換をもたらし、該置換がステロイドおよび非−ステロイドリガンドに応答して活性の増大をもたらす、宿主細胞中で発現させることができる遺伝子発現カセットを含む遺伝子発現変調システム。 - さらに、脊椎動物レチノイドX受容体リガンド結合ドメイン、無脊椎動物レチノイドX受容体リガンド結合ドメイン、ウルトラスピラクル蛋白質リガンド結合ドメイン、および2つのポリペプチド断片(ここで、第1のポリペプチド断片は脊椎動物レチノイドX受容体リガンド結合ドメイン、無脊椎動物レチノイドX受容体リガンド結合ドメイン、またはウルトラスピラクル蛋白質リガンド結合ドメインからのものであり、第2のポリペプチド断片は異なる脊椎動物レチノイドX受容体リガンド結合ドメイン、無脊椎動物レチノイドX受容体リガンド結合ドメイン、またはウルトラスピラクル蛋白質リガンド結合ドメインからのものである)を含むキメラリガンド結合ドメインよりなる群から選択される第2の核受容体リガンド結合ドメインを含む請求項1に記載の遺伝子発現変調システム。
- (a)i)その発現を変調すべき遺伝子と関連した応答エレメントを認識するDNA−結合ドメイン;および
ii)核受容体リガンド結合ドメイン
を含む第1のポリペプチドをコードするポリヌクレオチドを含む、宿主細胞中で発現させることができる第1の遺伝子発現カセット;
(b)i)トランス活性化ドメイン;および
ii)核受容体リガンド結合ドメイン
を含む第2のポリペプチドをコードするポリヌクレオチドを含む、宿主細胞中で発現させることができる第2の遺伝子発現カセット;ならびに
(c)i)DNA結合ドメインによって認識される応答エレメント;
ii)トランス活性化ドメインによって活性化されるプロモーター;および
iii)その発現が変調されるべき遺伝子
を含むポリヌクレオチド
を含み、該核受容体リガンド結合ドメインのうちの1つは、
a)配列番号:1のアミノ酸残基107、
b)配列番号:1のアミノ酸残基175、
c)配列番号:1のアミノ酸残基107および175、
d)配列番号:1のアミノ酸残基107および127、
e)配列番号:1のアミノ酸残基127および175、
f)配列番号:1のアミノ酸残基107、127、および175、または
g)配列番号:1のアミノ酸残基52、107および175
におけるアミノ酸残基の置換突然変異を含むグループH核受容体リガンド結合ドメインであり、該置換突然変異が、ステロイドおよび非−ステロイドリガンドに応答して活性の増大をもたらす、遺伝子発現変調システム。 - 該グループH核受容体リガンド結合ドメインが、エクジソン受容体リガンド結合ドメイン、ユビキタス受容体リガンド結合ドメイン、オーファン受容体1リガンド結合ドメイン、NER−1リガンド結合ドメイン、ステロイドホルモン核受容体1リガンド結合ドメイン、レチノイドX受容体相互作用蛋白質−15リガンド結合ドメイン、肝臓X受容体βリガンド結合ドメイン、ステロイドホルモン受容体様蛋白質リガンド結合ドメイン、肝臓X受容体リガンド結合ドメイン、肝臓X受容体αリガンド結合ドメイン、ファルネソイドX受容体リガンド結合ドメイン、受容体相互作用蛋白質14リガンド結合ドメイン、またはファルネゾール受容体リガンド結合ドメインである請求項1または3に記載の遺伝子発現変調システム。
- 置換突然変異を含むグループH核受容体リガンド結合ドメインがエクジソン受容体リガンド結合ドメインである請求項1または3に記載の遺伝子発現変調システム。
- 該DNA−結合ドメインがエクジソン受容体DNA−結合ドメイン、GAL4 DNA−結合ドメイン、およびLexA DNA−結合ドメインよりなる群から選択される請求項1または3に記載の遺伝子発現変調システム。
- トランス活性化ドメインがエクジソン受容体トランス活性化ドメイン、VP16トランス活性化ドメイン、B42酸性アクチベータトランス活性化ドメイン、およびp65トランス活性化ドメインよりなる群から選択される請求項1または3に記載の遺伝子発現変調システム。
- a)トランス活性化ドメイン、DNA−結合ドメイン、および置換突然変異を含むグループH核受容体リガンド結合ドメインを含むポリペプチド、
b)DNA−結合ドメイン、および置換突然変異を含むグループH核受容体リガンド結合ドメインを含むポリペプチド、および
c)トランス活性化ドメイン、および
a)配列番号:1のアミノ酸残基107、
b)配列番号:1のアミノ酸残基175、
c)配列番号:1のアミノ酸残基107および175、
d)配列番号:1のアミノ酸残基107および127、
e)配列番号:1のアミノ酸残基127および175、
f)配列番号:1のアミノ酸残基107、127、および175、または
g)配列番号:1のアミノ酸残基52、107および175
におけるアミノ酸残基の置換突然変異を含むグループH核受容体リガンド結合ドメインを含むポリペプチド
よりなる群から選択されるポリペプチドをコードするポリヌクレオチドを含み、該置換突然変異が、ステロイドおよび非−ステロイドリガンドに応答して活性の増大をもたらす、遺伝子発現カセット。 - 置換突然変異を含むグループH核受容体リガンド結合ドメインをコードする単離されたポリヌクレオチドであって、
a)配列番号:1のアミノ酸残基107、
b)配列番号:1のアミノ酸残基175、
c)配列番号:1のアミノ酸残基107および175、
d)配列番号:1のアミノ酸残基107および127、
e)配列番号:1のアミノ酸残基127および175、
f)配列番号:1のアミノ酸残基107、127、および175、または
g)配列番号:1のアミノ酸残基52、107および175
におけるアミノ酸残基の置換をもたらすコドン突然変異を含み、該置換突然変異が、ステロイドおよび非−ステロイドリガンドに応答して活性の増大をもたらす、単離されたポリヌクレオチド。 - 転写調節エレメントに作動可能に連結した請求項9に記載の単離されたポリヌクレオチドを含む発現ベクター。
- 該転写調節エレメントが宿主細胞中で作動する請求項10に記載の発現ベクターを含む単離された宿主細胞。
- 請求項9に記載の単離されたポリヌクレオチドによってコードされる単離されたポリペプチド。
- 置換突然変異を含むグループH核受容体リガンド結合ドメインを含む単離されたポリペプチドであって、該置換突然変異が
a)配列番号:1のアミノ酸残基107、
b)配列番号:1のアミノ酸残基175、
c)配列番号:1のアミノ酸残基107および175、
d)配列番号:1のアミノ酸残基107および127、
e)配列番号:1のアミノ酸残基127および175、
f)配列番号:1のアミノ酸残基107、127、および175、または
g)配列番号:1のアミノ酸残基52、107および175
におけるものであり、該置換突然変異が、ステロイドおよび非−ステロイドリガンドに応答して活性の増大をもたらす、単離されたポリペプチド。 - a)請求項1または3に記載の遺伝子発現変調システムを単離された宿主細胞に導入し;さらに、
b)該単離された宿主細胞にリガンドを導入する;
工程を含み、
変調すべき遺伝子が:
i)DNA結合ドメインによって認識される応答エレメント;
ii)トランス活性化ドメインによって活性化されるプロモーター;および
iii)その発現が変調されるべき遺伝子
を含む遺伝子発現カセットの構成要素であり、
それにより、該宿主細胞へのリガンドの導入に際して、b)iii)の遺伝子の発現が変調されることを特徴とする、単離された宿主細胞において遺伝子の発現を変調する方法。 - 該リガンドが、
a)式:
R1はH、Me、Et、i−Pr、F、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CH2OMe、CH2CN、CN、C≡CH、1−プロピニル、2−プロピニル、ビニル、OH、OMe、OEt、シクロプロピル、CF2CF3、CH=CHCN、アリル、アジド、SCNまたはSCHF2であり;
R2はH、Me、Et、n−Pr、i−Pr、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CH2OMe、CH2CN、CN、C≡CH、1−プロピニル、2−プロピニル、ビニル、Ac、F、Cl、OH、OMe、OEt、O−n−Pr、OAc、NMe2、NEt2、SMe、SEt、SOCF3、OCF2CF2H、COEt、シクロプロピル、CF2CF3、CH=CHCN、アリル、アジド、OCF3、OCHF2、O−i−Pr、SCN、SCHF2、SOMe、NH−CNであるか、またはR3、ならびにR2およびR3が結合したフェニル炭素と一緒になって、エチレンジオキシ、フェニル炭素に隣接した酸素を持つジヒドロフリル環、もしくはフェニル炭素に隣接した酸素を持つジヒドロピリル環を形成し;
R3はH、Etであるか、またはR2、ならびにR2およびR3が結合したフェニル炭素と一緒になって、エチレンジオキシ、フェニル炭素に隣接した酸素を持つジヒドロフリル環、もしくはフェニル炭素に隣接した酸素を持つジヒドロピリル環を形成し;
R4、R5およびR6は独立してH、Me、Et、F、Cl、Br、ホルミル、CF3、CHF2、CHCl2、CH2F、CH2Cl、CH2OH、CN、C≡CH、1−プロピニル、2−プロピニル、ビニル、OMe、OEt、SMeまたはSEtである)
の化合物;または
b)エクジソン、20−ヒドロキシエクジソン、ポナステロンA、ムリステロンA、オキシステロール、22(R)ヒドロキシコレステロール、24(S)ヒドロキシコレステロール、25−エポキシコレステロール、T0901317、5−アルファ−6−アルファ−エポキシコレステロール−3−スルフェート、7−ケトコレステロール−3−スルフェート、ファルネゾール、胆汁酸、1,1−ビスフォスフォネートエステル、または幼若ホルモンIII
である請求項14に記載の方法。 - さらに、単離された宿主細胞に第2のリガンドを導入することを含み、第2のリガンドが9−シス−レチノイン酸またはレチノイン酸の合成アナログである請求項14に記載の方法。
- 請求項1または請求項3に記載の遺伝子発現変調システムを含む単離された宿主細胞。
- 請求項17に記載の宿主細胞を含む非−ヒト生物。
- 置換突然変異が、配列番号:1のV107I、R175E、V107I/R175E、V107I/Y127E、Y127E/R175E、V107I/Y127E/R175E、またはT52V/V107I/R175E置換突然変異である、請求項1または3に記載の遺伝子発現変調システム。
- コドン突然変異が、配列番号:1のV107I、R175E、V107I/R175E、V107I/Y127E、Y127E/R175E、V107I/Y127E/R175E、またはT52V/V107I/R175E置換突然変異の置換突然変異をもたらす、請求項8に記載の遺伝子発現カセット。
- コドン突然変異が、配列番号:1のV107I、R175E、V107I/R175E、V107I/Y127E、Y127E/R175E、V107I/Y127E/R175E、またはT52V/V107I/R175E置換突然変異の置換突然変異をもたらす、請求項9に記載の単離されたポリヌクレオチド。
- 置換突然変異が、配列番号:1のV107I、R175E、V107I/R175E、V107I/Y127E、Y127E/R175E、V107I/Y127E/R175E、またはT52V/V107I/R175E置換突然変異である、請求項13に記載の単離されたポリペプチド。
- 置換突然変異が、配列番号:1のV107I/Y127E置換突然変異である、請求項1または3に記載の遺伝子発現変調システム。
- 置換突然変異が、配列番号:1のV107I/Y127E置換突然変異である、請求項8に記載の遺伝子発現カセット。
- 置換突然変異が、配列番号:1のV107I/Y127E置換突然変異である、請求項9に記載の単離されたポリヌクレオチド。
- 置換突然変異が、配列番号:1のV107I/Y127E置換突然変異である、請求項13に記載の単離されたポリペプチド。
- 前記エクジソン受容体リガンド結合ドメインが、無脊椎動物エクジソン受容体リガンド結合ドメイン、節足動物エクジソン受容体リガンド結合ドメイン、鱗翅目エクジソン受容体リガンド結合ドメイン、双翅目エクジソン受容体リガンド結合ドメイン、直翅目エクジソン受容体リガンド結合ドメイン、同翅目エクジソン受容体リガンド結合ドメイン、半翅目エクジソン受容体リガンド結合ドメイン、ハマキガ科のガ Choristoneura fumiferana(トウヒシントメハマキ)エクジソン受容体リガンド結合ドメイン、甲虫 Tenebrio molitor(チャイロコメノゴミムシダマシ)エクジソン受容体リガンド結合ドメイン、Manduca sexta(タバコスズメガ)エクジソン受容体リガンド結合ドメイン、Heliothies virescens(オオタバコガ)エクジソン受容体リガンド結合ドメイン、ユスリカ Chironomus tentans(キミドリユスリカ)エクジソン受容体リガンド結合ドメイン、カイコガ Bombyx moriエクジソン受容体リガンド結合ドメイン、ヤブニラミブッシュブラウン Bicyclus anynanaエクジソン受容体リガンド結合ドメイン、トチノキ Junonia coenia(アメリカタテハモドキ)エクジソン受容体リガンド結合ドメイン、ミバエ Drosophila melanogaster(キイロショウジョウバエ)エクジソン受容体リガンド結合ドメイン、カ Aedes aegypti(ネッタイシマカ)エクジソン受容体リガンド結合ドメイン、クロバエ Lucilia capitataエクジソン受容体リガンド結合ドメイン、クロバエ Lucilia cuprina(ヒツジキンバエ)エクジソン受容体リガンド結合ドメイン、クロバエ Calliphora vicinia(ホホアカクロバエ)エクジソン受容体リガンド結合ドメイン、地中海ミバエ Ceratitis capitata(チチュウカイミバエ)エクジソン受容体リガンド結合ドメイン、バッタ Locusta migratoria(トノサマバッタ)エクジソン受容体リガンド結合ドメイン、アブラムシ Myzus persicae(モモアカアブラムシ)エクジソン受容体リガンド結合ドメイン、シオマネキ Celuca pugilatorエクジソン受容体リガンド結合ドメイン、マダニ Amblyomma americanumエクジソン受容体リガンド結合ドメイン、コナジラミ Bamecia argentifoli(シルバーリーフコナジラミ)エクジソン受容体リガンド結合ドメイン、およびヨコバイNephotetix cincticeps(ツマグロヨコバイ)エクジソン受容体リガンド結合ドメインよりなる群から選択される、請求項1または3に記載の遺伝子発現変調システム。
- 前記エクジソン受容体リガンド結合ドメインが、ハマキガ科のガ Choristoneura fumiferana(トウヒシントメハマキ)エクジソン受容体リガンド結合ドメインである、請求項27に記載の遺伝子発現変調システム。
- 請求項1または3に記載の遺伝子発現変調システムを含むベクター。
- 前記ベクターが発現ベクターである、請求項29に記載のベクター。
- 前記ベクターがプラスミドである、請求項29に記載のベクター。
- 前記ベクターがウイルスベクターである、請求項29に記載のベクター。
- 前記ウイルスベクターがアデノウイルスベクターである、請求項32に記載のベクター。
- 請求項29に記載のベクターを含む宿主細胞。
- 請求項1または3に記載の遺伝子発現変調システムを含む宿主細胞。
- 前記宿主細胞が、細菌細胞、真菌類細胞、線虫細胞、昆虫細胞、魚類細胞、植物細胞、鳥類細胞、動物細胞、無脊椎動物細胞、脊椎動物細胞、酵母細胞、真核生物細胞、または哺乳動物細胞である、請求項34または35に記載の宿主細胞。
- 前記宿主細胞が、アスペルギルス(Aspergillus)細胞、トリコデルマ(Trichoderma)細胞、サッカロミセス(Saccharomyces)細胞、ピチア(Pichia)細胞、カンジダ(Candida)細胞、およびハンゼヌラ(Hansenula)細胞よりなる群から選択される酵母細胞である、請求項36に記載の宿主細胞。
- 前記宿主細胞が、シネコシスティス(Synechocystis)細胞、シネココッカス(Synechococcus)細胞、サルモネラ(Salmonella)細胞、バチルス(Bacillus)細胞、アシネトバクター(Acinetobacter)細胞、ロドコッカス(Rhodococcus)細胞、ストレプトマイセス(Streptomyces)細胞、大腸菌(Escherichia)細胞、シュードモナス(Pseudomonas)細胞、メチロモナス(Methylomonas)細胞、メチロバクター(Methylobacter)細胞、アルカリゲネス(Alcaligenes)細胞、シネコシスティス(Synechocystis)細胞、アナベナ(Anabaena)細胞、チオバチルス(Thiobacillus)細胞、メタノバクテリウム(Methanobacterium)細胞、およびクレブシエラ(Klebsiella)細胞よりなる群から選択される細菌細胞である、請求項36に記載の宿主細胞。
- 前記宿主細胞が植物細胞である、請求項36に記載の宿主細胞。
- 前記植物細胞が、リンゴ細胞、シロイヌナズナ(Arabidopsis)細胞、パールミレット細胞、バナナ細胞、大麦細胞、豆類細胞、ビート細胞、ブラックグラム細胞、ヒヨコマメ細胞、トウガラシ細胞、キュウリ細胞、ナス細胞、ソラマメ細胞、トウモロコシ細胞、メロン細胞、キビ細胞、ヤエナリ細胞、オート麦細胞、オクラ細胞、キビ(Panicum)細胞、パパイヤ細胞、落花生細胞、エンドウ細胞、コショウ細胞、ハトマメ細胞、パイナップル細胞、インゲンマメ(Phaseolus)細胞、ジャガイモ細胞、カボチャ細胞、米細胞、ソルガム細胞、大豆細胞、スカッシュ細胞、サトウキビ細胞、サトウダイコン細胞、ヒマワリ細胞、サツマイモ細胞、茶細胞、トマト細胞、タバコ細胞、スイカ細胞、および小麦細胞よりなる群から選択される、請求項39に記載の宿主細胞。
- 前記宿主細胞が哺乳動物細胞である、請求項36に記載の宿主細胞。
- 前記哺乳動物細胞が、ハムスター細胞、マウス細胞、ラット細胞、ウサギ細胞、ネコ細胞、イヌ細胞、ウシ細胞、ヤギ細胞、メウシ細胞、ブタ細胞、ウマ細胞、ヒツジ細胞、サル細胞、チンパンジー細胞、およびヒト細胞よりなる群から選択される、請求項41に記載の宿主細胞。
- 前記哺乳動物細胞がヒト細胞である、請求項42に記載の宿主細胞。
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EP2275558A3 (en) | 2011-04-06 |
JP2009106296A (ja) | 2009-05-21 |
EP2275558A2 (en) | 2011-01-19 |
US20130244330A1 (en) | 2013-09-19 |
JP2004524027A (ja) | 2004-08-12 |
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US9029152B2 (en) | 2015-05-12 |
US20080301825A1 (en) | 2008-12-04 |
WO2002066612A3 (en) | 2003-10-30 |
CA2445796C (en) | 2014-09-16 |
JP4328094B2 (ja) | 2009-09-09 |
EP1373470B1 (en) | 2013-04-24 |
US8669051B2 (en) | 2014-03-11 |
US8691527B2 (en) | 2014-04-08 |
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US8715959B2 (en) | 2014-05-06 |
CA2445796A1 (en) | 2002-08-29 |
WO2002066612A2 (en) | 2002-08-29 |
AU2002306550B2 (en) | 2007-10-25 |
US20060100416A1 (en) | 2006-05-11 |
EP3470520A2 (en) | 2019-04-17 |
EP1373470A4 (en) | 2007-04-11 |
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