JP2009106297A - 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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Abstract
【解決手段】遺伝子治療、蛋白質および抗体の大規模生産、細胞−ベースの高スループットスクリーニングアッセイ、機能的ゲノミクスおよびトランスシェニック生物における特性の調節のような適用のための宿主細胞において遺伝子の発現を変調する方法。置換突然変異を含むグループB核受容体リガンド結合ドメインを含む新規な核受容体ベースの誘導性遺伝子発現システムであって、そのような置換突然変異の効果がリガンド結合活性またはリガンド感受性を増大させることができ、それは、ステロイドまたは非−ステロイド特異的であり、宿主細胞において注目する遺伝子の発現を変調するのに有用なグループB核受容体−ベースの誘導性遺伝子発現システム。
【選択図】図1
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。
かくして、出願人らは、グループB−ベースの誘導性遺伝子発現システムにおけるリガンド感受性および誘導の大きさに影響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B核受容体(ここでは、「置換突然変異体」という)の構築、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という証明を記載する。本明細書中で提示するように、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の使用は、適用に応じてリガンド感受性およびトランス活性化の大きさを所望により選択することができる、原核生物および真核生物両宿主細胞におけ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、宿主細胞において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、遺伝子発現カセットは、置換突然変異を含むグループB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ことができ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B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、それらが含むポリヌクレオチド、およびそれら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。かくして、本発明は、置換突然変異を含むグループB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B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B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;さらに、b)該宿主細胞にリガンドを導入する工程を含み、ここに、変調すべき遺伝子は、i)該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)該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ことを特徴とする宿主細胞において遺伝子の発現を変調する方法を提供する。
Eは第三級炭素を含有する(C4−C6)アルキルまたは第三級炭素を含有するシアノ(C3−C5)アルキルであり;
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。
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、栄養補給食品、抗原、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な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り得る。
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検出することによる、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、置換突然変異を含むグループB核受容体リガンド結合ドメインを含む新規な核受容体−ベースの誘導性遺伝子発現システムを開発した。出願人らは、そのような置換突然変異の効果はリガンド結合活性またはリガンド感受性を増加させることができ、それはステロイドまたは非−ステロイド特異的であることを示した。かくして、出願人らの発明は、宿主細胞において注目する遺伝子の発現の変調に有用なグループB核受容体−ベースの誘導性遺伝子発現システムを提供する。出願人らの新規な誘導性遺伝子発現システムおよび宿主細胞において遺伝子発現を変調する方法におけるその使用は、現在入手可能な誘導性発現システムの制限を克服し、当業者に、遺伝子発現を制御するための効果的な手段を提供する。
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。
遺伝子発現カセット:遺伝子発現カセット(スイッチ)は、当該分野で入手できる標準的なクローニング方法を用いて以下のように構築した。以下に、本明細書中に記載する実施例で用いる各スイッチの調製および組成を簡単に記載する。
RXRトランス活性化の活性を修飾する努力において、配列比較に基づいて重要であると予測されたRXRリガンド結合ドメイン内の残基を、2つの異なる生物からのRXRにおいて突然変異させた。表1および2は、突然変異させ、トランス活性化能力の修飾につき調べた、MmRXRαおよびHsRXRβのリガンド結合ドメイン内の各々のアミノ酸残基を示す。
Claims (22)
- a)i)トランス活性化ドメインと;
ii)その発現が変調されるべき遺伝子と関連した応答エレメントを認識するDNA−結合ドメインと;
iii)置換突然変異を含むグループB核受容体リガンド結合ドメインと
を含む第一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、および
b)エクジソン受容体、ユビキタス受容体、オーファン受容体1、ステロイドホルモン核受容体1、レチノイドX受容体相互作用蛋白質−15、肝臓X受容体β、ステロイドホルモン受容体様蛋白質、肝臓X受容体、肝臓X受容体α、ファルネソイドX受容体、受容体相互作用蛋白質14、およびファルネゾール受容体よりなる群から選択される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
を含む遺伝子発現変調システム。 - a)i)その発現を変調させるべき遺伝子と関連した応答エレメントを認識するDNA−結合ドメインと;
ii)核受容体リガンド結合ドメインと
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;および
b)i)トランス活性化ドメインと;
ii)核受容体リガンド結合ドメインと
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
を含み、ここに、該核受容体リガンド結合ドメインのうちの1つは、置換突然変異を含むグループB核受容体リガンド結合ドメインである遺伝子発現変調システム。 - 該グループB核受容体リガンド結合ドメインが、レチノイドX受容体、H−2領域II結合蛋白質(H−2RIIBP)、核受容体コレギュレーター−1(RCoR−1)、ウルトラスピラクル蛋白質、2C1核受容体、および漿膜因子1(CF−1)よりなる群から選択される、請求項1または2記載の遺伝子発現変調システム。
- グループB核受容体リガンド結合ドメインが、アミノ酸残基の置換をもたらすコドン突然変異を含むポリヌクレオチドによってコードされ、ここに、該アミノ酸残基が、a)配列番号:1の401または429、b)配列番号:1の401および429、c)配列番号:2の337、344、355、385、431、442、462、470、472、473、495、500、511、516または528、d)配列番号:2の321、322および323、e)配列番号:2の450、451および452、f)配列番号:2の455、456、457および458、g)配列番号:2の470、472および473、h)配列番号:2の475、476、477、478および479、ならびにi)配列番号:2の481、482および483と同等または類似の位置にある、請求項3記載の遺伝子発現変調システム。
- 置換突然変異を含む該グループB核受容体リガンド結合ドメインが、レチノイドX受容体リガンド結合ドメインである、請求項4記載の遺伝子発現変調システム。
- 置換突然変異が、a)配列番号:1のE401DまたはG429S、b)配列番号:1のE401DおよびG429S、c)配列番号:2のT337S、D344N、K355R、S385A、M431L、R442K、V462L、S470A、E471D、T473E、A495S、E500S、K511R、T516VまたはA528S、d)配列番号:2のG321L、P322RおよびG323V、e)配列番号:2のD450E、A451VおよびK452R、f)配列番号:2のS455K、N456S、P457AおよびS458Q、g)配列番号:2のS470A、E472DおよびT473Y、h)配列番号:2のC475T、K476R、Q477T、K478TおよびY479H、ならびにi)配列番号:2のE481D、Q482EおよびQ483Pよりなる群から選択される、請求項5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2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酸性アクチベーター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2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B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B核受容体リガンド結合ドメインを含むポリペプチド、ならびに
c)トランス活性化ドメイン、および置換突然変異を含むグループB核受容体リガンド結合ドメインを含むポリペプチド
から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む遺伝子発現カセット。 - 置換突然変異を含むグループB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401または429、b)配列番号:1の401および429、c)配列番号:2の337、344、355、385、431、442、462、470、472、473、495、500、511、516または528、d)配列番号:2の321、322および323、e)配列番号:2の450、451および452、f)配列番号:2の455、456、457および458、g)配列番号:2の470、472および473、h)配列番号:2の475、476、477、478および479、ならびにi)配列番号:2の481、482および483と同等または類似の位置にあるアミノ酸残基の置換をもたらすコドン突然変異を含む単離されたポリヌクレオチド。
- 該コドン突然変異が、a)配列番号:1のE401DまたはG429S、b)配列番号:1のE401DおよびG429S、c)配列番号:2のT337S、D344N、K355R、S385A、M431L、R442K、V462L、S470A、E471D、T473E、A495S、E500S、K511R、T516VまたはA528S、d)配列番号:2のG321L、P322RおよびG323V、e)配列番号:2のD450E、A451VおよびK452R、f)配列番号:2のS455K、N456S、P457AおよびS458Q、g)配列番号:2のS470A、E472DおよびT473Y、h)配列番号:2のC475T、K476R、Q477T、K478TおよびY479H、ならびにi)配列番号:2のE481D、Q482EおよびQ483Pよりなる群から選択される置換突然変異をもたらす、請求項10記載の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10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できる、請求項12記載の発現ベクターを含む宿主細胞。
- 請求項10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B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401または429、b)配列番号:1の401および429、c)配列番号:2の337、344、355、385、431、442、462、470、472、473、495、500、511、516または528、d)配列番号:2の321、322および323、e)配列番号:2の450、451および452、f)配列番号:2の455、456、457および458、g)配列番号:2の470、472および473、h)配列番号:2の475、476、477、478および479、ならびにi)配列番号:2の481、482および483と同等または類似の位置にあ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B核受容体リガンド結合ドメインがレチノイドX受容体リガンド結合ドメインである、請求項15記載の単離されたポリペプチド。
- 該突然変異が、a)配列番号:1のE401DまたはG429S、b)配列番号:1のE401DおよびG429S、c)配列番号:2のT337S、D344N、K355R、S385A、M431L、R442K、V462L、S470A、E471D、T473E、A495S、E500S、K511R、T516VまたはA528S、d)配列番号:2のG321L、P322RおよびG323V、e)配列番号:2のD450E、A451VおよびK452R、f)配列番号:2のS455K、N456S、P457AおよびS458Q、g)配列番号:2のS470A、E472DおよびT473Y、h)配列番号:2のC475T、K476R、Q477T、K478TおよびY479H、ならびにi)配列番号:2のE481D、Q482EおよびQ483Pよりなる群から選択される、請求項16記載の単離されたポリペプチド。
- a)請求項1または2記載の遺伝子発現変調システムを宿主細胞に導入し;さらに、
b)宿主細胞にリガンドを導入する
工程を含み、ここに、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と;
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と;
iii)その発現が変調されるべき遺伝子と
を含む遺伝子発現カセットの構成要素であり、
該リガンドの宿主細胞への導入に際して、b)iii)の遺伝子の発現が変調される、宿主細胞中で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、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する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する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;
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;
b)エクジソン、20−ヒドロキシエクジソン、ポナステロンA、またはムリステロンA;
c)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−ビフォスフォネートエステル、または幼若ホルモンIII;または
d)9−シス−レチノイン酸、4−(1−(3,5,5,8,8−ペンタメチル−5,6,7,8−テトラヒドロ−2−ナフチル)−エテニル)安息香酸(3−メチル−TTEB)、((E)−2)2−(5,6,7,8−テトラヒドロ−3,5,5,8,8−ペンタメチル−2−ナフチル)プロペン−1−イル)−4−チオフェンカルボン酸)、2−(5,6,7,8−テトラヒドロ−3,5,5,8,8−テトラメチル−2−ナフチル)−2−(カルボキシフェニル)−1,3−ジオキソラン、4−(5H−2,3−(2,5−ジメチル−2、5−ヘキサノ)−5−メチル−ジベンゾ(b,e)(1,4)ジアゼピン−11−イル)−安息香酸(HX600)もしくはそのチアジアゼピンアナログ、3,7,11,15−テトラメチルヘキサデコン酸(フィタン酸)、6−(1−(3,5,5,8,8−ペンタメチル−5,6,7,8−テトラヒドロナフタレン−2−イル)シクロプロピル)ニコチン酸、2−(4−カルボキシフェニル)−2−(5,6,7,8−テトラヒドロ−5,5,8,8−テトラメチル−2−ナフタレニル)−1,3−ジチアン、または4−(2−メチル)−1−(5,6,7,8−テトラヒドロ−5,5,8,8−テトラメチル−2−ナフタレニル)プロペニル)安息香酸
である、請求項18記載の方法。 - さらに宿主細胞に第2のリガンドを導入することを含み、該第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18記載の方法(9−シス−レチノイン酸およびレチノイン酸の合成アナログを同時に加える状況であれば(リガンド1および2?として))。
- 請求項1または2記載の遺伝子発現変調システムを含む宿主細胞。
- 請求項21記載の宿主細胞を含む非−ヒト生物。
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US9249207B2 (en) | 2016-02-02 |
US20170015728A1 (en) | 2017-01-19 |
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JP4994563B2 (ja) | 2012-08-08 |
EP1534738A2 (en) | 2005-06-01 |
DK1534738T3 (da) | 2012-10-01 |
WO2002066615A9 (en) | 2004-01-29 |
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WO2002066615A3 (en) | 2005-04-07 |
CA2438133C (en) | 2015-01-27 |
WO2002066615A2 (en) | 2002-08-29 |
JP2004533216A (ja) | 2004-11-04 |
EP1534738A4 (en) | 2007-05-09 |
US10087231B2 (en) | 2018-10-02 |
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