JPWO2013172421A1 - Ampkタンパク質活性化剤のスクリーニング方法及びampkタンパク質活性化剤 - Google Patents
Ampkタンパク質活性化剤のスクリーニング方法及びampkタンパク質活性化剤 Download PDFInfo
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Abstract
Description
被検化合物の存在下で、PHBタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるPHBタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるPHBタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備える。
担体上に固定した、PHBタンパク質及びAMPKタンパク質のいずれか一方のタンパク質に、
被検化合物を含有する溶液並びにPHBタンパク質及びAMPKタンパク質の他方のタンパク質を含有する溶液を添加する工程と、
前記溶液を除去した後、PHBタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるPHBタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるPHBタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備えることができる。
担体上に固定した、PHBタンパク質及びAMPKタンパク質のいずれか一方のタンパク質に被検化合物を含有する溶液を添加する工程と、
PHBタンパク質及びAMPKタンパク質の他方のタンパク質を含有する溶液を添加する工程と、
前記溶液を除去した後、PHBタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるPHBタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるPHBタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備えることができる。
ヒト肝癌由来細胞株HepG2細胞にヒトPHB1或いはヒトPHB2に対するsiRNA(Stealth RNAi、Invitrogen社)をLipofectamine RNAiMAX(Invitrogen社)を用いてトランスフェクションした。
siPHB1:5’−UUGGCAAUCAGCUCAGCUGCCUUGG−3’(配列番号1)
5’−CCAAGGCAGCUGAGCUGAUUGCCAA−3’(配列番号2)
siPHB2:5’−UACGAUUCUGUGAUGUGGCGAUCGU−3’(配列番号3)
5’−ACGAUCGCCACAUCACAGAAUCGUA−3’(配列番号4)
ヒト肝癌由来細胞株HepG2細胞にヒトPHB1或いはヒトPHB2に対するsiRNA(Stealth RNAi、Invitrogen社)をLipofectamine RNAiMAX (Invitrogen社)を用いてトランスフェクションした。トランクフェクション72時間後、細胞を溶解バッファー(1%NP−40、25mM Tris−HCl pH7.4、10mM EDTA、10mM EGTA、100mMフッ化ナトリウム、10mMピロリン酸ナトリウム、10mMオルトバナジン酸ナトリウム、10mMβ−グリセロリン酸、pH7.4)で溶解し、細胞抽出液とした。得られた細胞抽出液を用いてSDS−PAGEを実施し、細胞抽出液に含まれるタンパク質を大きさにより分離した。その後、分離したタンパク質をPVDFメンブレンに転写し、抗リン酸化AMPKα抗体及び抗AMPKα抗体(いずれもCell Signaling Technology社)、抗PHB1抗体(SantaCruz Biotechnology社)、抗PHB2抗体(Millipore社)によりウェスタンブロッティングを行った。
PHBタンパク質が相互作用を介してAMPKタンパク質の制御に関与する可能性を検討するため、共免疫沈降を行った。陰性コントロールとして抗IgG抗体を用いた。
PHBタンパク質とAMPKタンパク質の直接相互作用の可能性を、GSTプルダウン法を用いて検討した。
GSTプルダウン法を用いて、PHBタンパク質と相互作用するAMPKタンパク質サブユニットを同定した。
AMPKタンパク質βサブユニットにおける、PHBタンパク質との相互作用に重要な領域を同定するため、AMPKタンパク質βサブユニットの欠損変異体を用いて以下の実験を行った。
GST−PHB1タンパク質(500ng)をGlutathione Sepharose 4 Fast Flow(10μL)に結合させ、GST担体−タンパク質複合体とした。GST担体−タンパク質複合体に化合物A(最終濃度10μM)及びAMPKタンパク質(100ng)を加え、NET Buffer(300μL)中で3時間、4℃にてインキュベートした。NETバッファーでGST担体−タンパク質複合体を洗浄後、サンプルバッファー(50μL)を添加してサンプルを調製した。得られたサンプルをSDS−PAGEにより分離した後、PVDFメンブレンに転写し、ウェスタンブロッティングを行い、AMPKタンパク質がGlutathione Sepharoseに結合したGSTタンパク質或いはGST−PHB1タンパク質と結合してプルダウンされるかを検出した。
HepG2細胞の培養系に化合物Aを各々の最終濃度となるように添加して、更に3時間培養した後、溶解バッファーで細胞を溶解し細胞抽出液とした。得られた細胞抽出液を用いてSDS−PAGEを実施し、抽出液に含まれるタンパク質を大きさに基づいて分離した後、PVDFメンブレンに転写し、ウェスタンブロッティングによりPHB1、PHB2、AMPKα及びリン酸化AMPKαを検出した。
Claims (14)
- プロヒビチンタンパク質とAMPKタンパク質との相互作用の阻害を指標とする、AMPKタンパク質活性化剤のスクリーニング方法。
- 被検化合物の存在下で、プロヒビチンタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備える、請求項1記載のスクリーニング方法。 - 担体上に固定した、プロヒビチンタンパク質及びAMPKタンパク質のいずれか一方のタンパク質に、
被検化合物並びにプロヒビチンタンパク質及びAMPKタンパク質の他方のタンパク質を含有する溶液を添加する工程と、
前記溶液を除去した後、プロヒビチンタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備える、請求項1記載のスクリーニング方法。 - 担体上に固定した、プロヒビチンタンパク質及びAMPKタンパク質のいずれか一方のタンパク質に、被検化合物を含有する溶液を添加する工程と、
プロヒビチンタンパク質及びAMPKタンパク質の他方のタンパク質を含有する溶液を添加する工程と、
前記溶液を除去した後、プロヒビチンタンパク質とAMPKタンパク質との相互作用を測定する工程と、
被検化合物の存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用が、被検化合物の非存在下におけるプロヒビチンタンパク質とAMPKタンパク質との相互作用より弱い場合に、当該被検化合物をAMPKタンパク質活性化剤と判定する工程と、
を備える、請求項1記載のスクリーニング方法。 - プロヒビチンタンパク質とAMPKタンパク質との相互作用を測定する方法が、近接効果(proximity effect)を利用する測定法である請求項1〜4のいずれか1項に記載のスクリーニング方法。
- プロヒビチンタンパク質がプロヒビチン1タンパク質である、請求項1〜5のいずれか一項に記載のスクリーニング方法。
- AMPKタンパク質がAMPKタンパク質βサブユニットである、請求項1〜6のいずれか一項に記載のスクリーニング方法。
- プロヒビチンタンパク質が融合タンパク質である、請求項1〜7のいずれか一項に記載のスクリーニング方法。
- AMPKタンパク質が融合タンパク質である、請求項1〜8のいずれか一項に記載のスクリーニング方法。
- 単離されたプロヒビチンタンパク質及び単離されたAMPKタンパク質を混合することにより形成されたプロヒビチンタンパク質−AMPKタンパク質複合体。
- 細胞内で過剰発現させたプロヒビチンタンパク質及び細胞内で過剰発現させたAMPKタンパク質が結合することにより形成されたプロヒビチンタンパク質−AMPKタンパク質複合体。
- プロヒビチンタンパク質とAMPKタンパク質との相互作用を阻害する化合物を有効成分とする、AMPKタンパク質活性化剤。
- プロヒビチンタンパク質がプロヒビチン1タンパク質である、請求項12に記載のAMPKタンパク質活性化剤。
- AMPKタンパク質がAMPKタンパク質βサブユニットである、請求項12又は13に記載のAMPKタンパク質活性化剤。
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IRYNA O. ZUBOVYCH ET AL.: "Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans", MOLECULAR BIOLOGY OF THE CELL, vol. 21, no. 6, JPN6013040047, March 2010 (2010-03-01), pages 956 - 969, XP055177912, ISSN: 0003523256, DOI: 10.1091/mbc.E09-08-0673 * |
J. CHOI ET AL.: "Sanguinarine is an allosteric activator of AMP-activated protein kinase", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 413, no. 2, JPN6013040048, 23 September 2011 (2011-09-23), pages 259 - 263, XP028391514, ISSN: 0003576158, DOI: 10.1016/j.bbrc.2011.08.081 * |
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US9863955B2 (en) | 2018-01-09 |
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