JP4955904B2 - 新規エクジソン受容体/無脊椎動物レチノイドx受容体−ベースの誘導性遺伝子発現システム - Google Patents
新規エクジソン受容体/無脊椎動物レチノイドx受容体−ベースの誘導性遺伝子発現システム 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、以前、トランス活性化およびDNA結合ドメインを2つの異なる蛋白質上に置くことによってそれらを分離する結果、リガンドの不存在下でバックグラウンド活性が大いに低下し、リガンドの存在下でバックグラウンドを超えて活性がかなり増加することを示した(係属中の出願PCT/US01/09050)。この2−ハイブリッドシステムは、国際特許出願PCT/US97/05330およびPCT/US98/14215に開示された2つのシステムと比較してかなり改良された誘導性遺伝子発現変調システムである。2−ハイブリッドシステムは、DNA結合ドメインが遺伝子上のDNA結合部位に結合した場合、トランス活性化ドメインがより効果的にプロモーターを活性化するように、DNA結合ドメインに対して転写活性化ドメインをより好都合な位置に運ぶ相互作用蛋白質の対の能力を開発する(例えば、米国特許第5,283,173号参照)。簡単に述べれば、2−ハイブリッド遺伝子発現システムは2つの遺伝子発現カセットを含み、第1のカセットは核受容体ポリペプチドに融合したDNA結合ドメインをコードし、第2のカセットは異なる核受容体ポリペプチドに融合したトランス活性化ドメインをコードする。リガンドの存在下において、第1のポリペプチドと第2のポリペプチドとの相互作用は、DNA結合ドメインをトランス活性化ドメインに効果的に連結させる。DNA結合およびトランス活性化ドメインは2つの異なる分子上に存在するので、リガンドの不存在下におけるバックグラウンド活性は大いに低下する。
本発明の新規なEcR/無脊椎動物RXR−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、各々、ハイブリッド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られる新規な遺伝子発現カセットも提供する。
本発明の新規なエクジソン受容体/無脊椎動物レチノイドX受容体ベースの誘導性遺伝子発現システムは、a)DNA結合ドメインまたはトランス活性化ドメイン、およびb)EcRリガンド結合ドメインまたは無脊椎動物RXRリガンド結合ドメインを含むハイブリッド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ハイブリッドポリペプチドは、宿主細胞内で遺伝子の発現を変調するためのEcR−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。
本発明の新規なエクジソン受容体/無脊椎動物レチノイドX受容体−ベースの誘導性遺伝子発現システムは、a)DNA結合ドメインまたはトランス活性化ドメイン、およびb)EcRリガンド結合ドメインまたは無脊椎動物RXRリガンド結合ドメインを含むハイブリッド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ハイブリッドポリペプチドは、宿主細胞内で遺伝子の発現を変調するためのEcR−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。
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)本発明による遺伝子発現変調システムを宿主細胞に導入し、次いで、b)リガンドを宿主細胞に導入する工程を含み、ここに、変調すべき遺伝子はi)第1のハイブリッドポリペプチドの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)第2のハイブリッドポリペプチド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。
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。
前記したごとく、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種々の注目する遺伝子の発現で有用であろう。かくして、出願人らの発明は、本発明による遺伝子発現システムを含む単離された宿主細胞を提供する。また、本発明は、本発明による遺伝子発現カセットを含む単離された宿主細胞を提供する。また、出願人らの発明は、本発明によるポリヌクレオチドまたはポリペプチドを含む単離された宿主細胞を提供する。単離された宿主細胞は原核生物または真核生物宿主細胞であってよい。
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。
一般的方法
本明細書中で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、Experimants 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.and Wiley−Interscience(1987)によって記載されている。
Claims (4)
- a)i)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;および
ii)エクジソン受容体リガンド結合ドメイン
を含む第1のハイブリッド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)非−鱗翅目、非−双翅目無脊椎動物レチノイドX受容体リガンド結合ドメイン
を含む第2のハイブリッドポリペプチドをコードするポリヌクレオチドを含む、宿主細胞で発現させることができる第2の遺伝子発現カセット;並びに
c)i)第1のハイブリッドポリペプチドのDNA−結合ドメインによって認識される応答エレメント;
ii)第2のハイブリッドポリペプチド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)その発現を変調させるべき遺伝子
を含む第3の遺伝子発現カセット
を含む遺伝子発現変調システムを含む単離された哺乳動物宿主細胞。 - 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)非−鱗翅目、非−双翅目無脊椎動物レチノイドX受容体リガンド結合ドメイン
を含む第1のハイブリッド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)エクジソン受容体リガンド結合ドメイン
を含む第2のハイブリッドポリペプチドをコードするポリヌクレオチドを含む、宿主細胞で発現させることができる第2の遺伝子発現カセット;並びに
c)i)第1のハイブリッドポリペプチドのDNA−結合ドメインによって認識される応答エレメント;
ii)第2のハイブリッドポリペプチド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
を含む第3の遺伝子発現カセット
を含む遺伝子発現変調システムを含む単離された哺乳動物宿主細胞。 - 該哺乳動物細胞がマウス細胞またはヒト細胞である請求項1記載の単離された哺乳動物宿主細胞。
- 哺乳動物細胞がマウス細胞またはヒト細胞である請求項2記載の単離された哺乳動物宿主細胞。
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US26979901P | 2001-02-20 | 2001-02-20 | |
US60/269,799 | 2001-02-20 | ||
US29481401P | 2001-05-31 | 2001-05-31 | |
US60/294,814 | 2001-05-31 | ||
PCT/US2002/005235 WO2002066613A2 (en) | 2001-02-20 | 2002-02-20 | Novel ecdysone receptor/invertebrate retinoid x receptor-based inducible gene expression system |
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JP2008304207A Expired - Fee Related JP5345372B2 (ja) | 2001-02-20 | 2008-11-28 | 新規エクジソン受容体/無脊椎動物レチノイドx受容体−ベースの誘導性遺伝子発現システム |
JP2013126817A Expired - Fee Related JP5887301B2 (ja) | 2001-02-20 | 2013-06-17 | 新規エクジソン受容体/無脊椎動物レチノイドx受容体−ベースの誘導性遺伝子発現システム |
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JP2013126817A Expired - Fee Related JP5887301B2 (ja) | 2001-02-20 | 2013-06-17 | 新規エクジソン受容体/無脊椎動物レチノイドx受容体−ベースの誘導性遺伝子発現システム |
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EP1456346A4 (en) | 2006-12-20 |
US9493540B2 (en) | 2016-11-15 |
CA2441444A1 (en) | 2002-08-29 |
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AU2008221578B2 (en) | 2012-05-03 |
ATE545705T1 (de) | 2012-03-15 |
PT1456346E (pt) | 2012-05-02 |
EP1456346B1 (en) | 2012-02-15 |
ES2385598T3 (es) | 2012-07-27 |
AU2002247184B2 (en) | 2008-06-19 |
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