JP4559222B2 - 改変インスリン様成長因子結合蛋白質 - Google Patents
改変インスリン様成長因子結合蛋白質 Download PDFInfo
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- JP4559222B2 JP4559222B2 JP2004520184A JP2004520184A JP4559222B2 JP 4559222 B2 JP4559222 B2 JP 4559222B2 JP 2004520184 A JP2004520184 A JP 2004520184A JP 2004520184 A JP2004520184 A JP 2004520184A JP 4559222 B2 JP4559222 B2 JP 4559222B2
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- igfbp
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Description
IGFBP-3 CDKKGFYKKKQCRPSKGRKRGFC [配列番号3] (Firth, 1998)
IGFBP-5 CDRKGFYKRKQCKPSRGRKRGIC [配列番号4] (Arai, 1996b)
IGFBP-2 CDKHGLYNLKQCKMSLNGQRGEC [配列番号5]
* * * *
IGFBP1 CNKNGFYHSRQCETSMDGEAGLC [配列番号6]
IGFBP4 CDRNGNFHPKQCHPALDGQRGKC [配列番号7]
IGFBP6 CDHRGFYRKRQCRSSQGQRRGPC [配列番号8]
*=保存された正帯電残基
PKKLRP [配列番号9] KHGLYNLKQCKMSLNGQR [配列番号14]
PAKLRP [配列番号10] AHGLYNLKQCKMSLNGQR [配列番号15]
PKALRP [配列番号11] KHGLYNLAQCKMSLNGQR [配列番号16]
PKKLAP [配列番号12] KHGLYNLKQCAMSLNGQR [配列番号17]
PAALAP [配列番号13] AHGLYNLAQCAMSLNGQR [配列番号18]
変異誘発とサブクローニング
pBluescriptベクター(Stratagene、La Jolla、CA、USA)においてhIGFBP−2をコードするcDNAの突然変異を、Quikchange突然変異誘発法(Stratagene)を用いて導入した。リシン(K)からアラニン(A)への変異および欠失変異Des(114〜170)Hisを導入するために、下記のオリゴヌクレオチドを使用した。
[SEQ ID No 19]
逆方向 5'AGG GGG TGG TCG CAG GGC GGC AGG CTC CTC CAG GCC AAG 3'
[SEQ ID No 20]
K227AHis 順方向 5'ATC CCC AAC TGT GAC GCC CAT GGC CTG TAC ACC 3'
[SEQ ID No 21]
逆方向 5'GGT GTA CAG GCC ATG GGC GTC ACA GTT GGG GAT 3'
[SEQ ID No 22]
K234AHis 順方向 5'GGC CTG TAC AAC CTC GCC CAG TGC AAG ATG TCT 3'
[SEQ ID No 23]
逆方向 5'AGA CAT CTT GCA CTG GGC GAG GTT GTA CAG GCC 3'
[SEQ ID No 24]
K237AHis 順方向 5'AAC CTC AAA CAG GCC ATG TCT CTG AAC GGG 3'
[SEQ ID No 25]
逆方向 5'CCC GTT CAG AGA CAT GGC GCA CTG TTT GAG GTT 3'
[SEQ ID No 26]
Des(114-170)His 順方向1 5'GTT GCA GAC AAT GGC GCC GGC CAC TCA GAA GAA GCC 3'
[SEQ ID No 27]
逆方向1 5'GCC TCC TTC TGA GTG GCC GGC GCC ATT GTC TGC AAC 3'
[SEQ ID No 28]
順方向2 5'CGG CAC ATG GGC AAG GCC GGC AAG CAT CAC CTT 3'
[SEQ ID No 29]
逆方向2 5'AAG GTG ATG CTT GCC GGC CTT GCC CAT GTG CCG 3'
[SEQ ID No 30]
各蛋白質のC末端の6ヒスチジンタグを利用して標準的なニッケル親和性精製法を用いて蛋白質を精製した。IGFBPが分泌されるので、精製は培地から行う(Forbesら、1998)。ニッケルカラムからの溶出に続いて、逆相高速液体クロマトグラフィー(HPLC)を用いて蛋白質をさらに精製した。純度は、rpHPLC、SDS PAGEおよび質量分析法によって解析した。各変異体の質量を、エレクトロスプレー質量分析法(Dr.Chris Bagley、Hanson Centreによる)によって求め、正確であることがわかった(一般的に質量分析の限界=1質量単位/10,000ダルトンの範囲内)。
hIGFBP−2および変異体のIGF結合親和性を、IGF−IまたはIGF−IIをセンサ表面に固定化したBIAcoreを使った表面プラズモン共鳴(surface plasmon resonance)によって求めた(方法の詳細は、Carrickら(2001)を参照されたい)。IGF−IまたはIGF−II(70RU)を、標準的な固定化の手順(LofasとJohnsson、1990)を用いてCM−5バイオセンサチップ(BIAcore Inc)にアミン基を介して固定化した。簡単に説明すると、5μl/分で、CM5チップを35μlのNHS(0.4mg)/EDC(2.6mg)で活性化し、35μlのIGF(10μg/ml)を10mM酢酸ナトリウムpH4.5中で固定化した。未反応の基を、35μlの1Mエタノールアミン−HCl、pH8.5で不活性化した。一定範囲のhIGFBP−2または変異体濃度(50、25、12.5、6.25および3.1nM)での速度論的研究を、結合に300秒、解離に900秒かけて、質量輸送(mass transport)の影響を最小にするために40μl/分で行った。IGF表面は10mMHClで再生処理した。
蛋白質加水分解試験のためのプロテアーゼの供給源は、癌細胞のならし培地(conditioned medium)であった。細胞は、ウシ胎児血清の存在下で密集するまで増殖させた。(T84細胞は、DMEM:10%ウシ胎児血清FBSとHamのF12(50:50v:v)中で増殖する。LNCaPは、RPMI+6%FBS中で増殖させた。PC3とDU145は、DMEM+10%FBS中で増殖させた。すべての培地とFBSはGIBCOからのものである)。その後、細胞を無血清培地で2×2時間洗浄した。その後、無血清条件で3日間培養し、培地を採取した。ならし培地を、セントリコン−10(centricon−10 )(Millipore Corp、MA USA)でおよそ10倍に濃縮した。精製されたhIGFBP−2またはその変異体(2μl中250ng)を37℃で24時間ならし培地と混合して、蛋白質加水分解を行わせた。蛋白質を、12%トリシンSDSポリアクリルアミドゲルで分離し、ニトロセルロースに移した。ニトロセルロースフィルターを、特異的ポリクローナル抗IGFBP−2抗体(我々の実験室で作製)でプローブしてIGFBP−2およびIGFBP−2断片を検出した。アビジンアルカリホスファターゼに結合させた2次ヤギ抗ウサギ抗体(Sigma)を用いて、抗IGFBP−2抗体を検出した。アビジンアルカリホスファターゼの基質(ニトロブルーテトラゾリウムと5 ブロモ 4 クロロ 3−インドリルリン酸 p−トルイジン塩)を加え、呈色したバンドはIGFBP−2の存在を示唆した。
ヘパリンを、ビオシチンヒドラジン(Pierce)を用い、その製造業者が推奨する条件を用いてビオチン化した。反応に続いて、ビオチン化されたヘパリンを、セントリコン−3(centricon−3 )(Millipore Corp、MA USA)を用いて濃縮し、H2Oに対して透析した。ビオチン化ヘパリンを、0.3M NaClおよびHBS(界面活性剤を含むHEPES緩衝生理食塩水、BIAcore Inc.)中でストレプトアビジンバイオセンサチップに固定化した。異なる濃度(6.25nMから300nM)のhIGFBP−2と変異体を10μl/分で注入した。表面の再生処理は2M NaClによって行なった。
細胞を、RPMI(GIBCO)+10%FCS(ウシ胎児血清)中の96ウェルプレートに1ウェル当たり細胞12000個で植え付け、2日間増殖させ、無血清RPMIで3時間洗浄し、その後RPMI+5%BSA中でブチレート(5mM、Sigma)またはブチレートと多様な濃度のIGF−Iとの組合せで処理する。この実験では、種々の量のIGFBP−2または変異体IGFBP−2をブチレート+IGF−1処理細胞に加えた。増殖は、PromegaのCell−titre−Gloキットを用いて測定する。これは基本的にはATPレベルを測定する。IGFは細胞をアポトーシスから救済し、結合蛋白質(天然あるいは変異体)は、細胞をアポトーシスから救済するIGFの能力を阻害する(IGFを受容体から隔離する)。
クローニング、発現、純度およびIGF結合親和性
5つの変異体を、プロテアーゼ抵抗性の導入またはマトリックス結合の妨害のために設計した(K180A K181AHis、K227AHis、K234AHis、K237AHis、Des(114〜170)His)。これらは、精製して均質化し(図2)、質量分析にかけ、期待した質量を有していることを確認した。残基K180とK181は、プロテアーゼ切断の潜在的部位であり(Ho,J.P.& Baxter,R.C.(1997)、またマトリックス結合に関与しているかもしれない(Hodgkinsonら(1994))。K227、K234およびK237は、マトリックス結合性モチーフに対応するIGFBP−3および−5の類似領域内の残基である。蛋白質加水分解性の切断およびマトリックス結合の潜在的部位は、図3でハイライト表示されている。
変異体結合蛋白質を、材料と方法で記述した分析法でプロテアーゼ感受性について分析した。我々はまず、切断型変異体Des(114〜170)Hisを解析し、T84、HT29、CaCO(すべての結腸癌細胞)およびPC3(前立腺癌細胞系)を含む多くのならし培地でプロテアーゼ抵抗性を観察した。表4は、どの細胞系が使用されたか、プロテアーゼ活性の相対量(ゲルの観察からの定性量)およびどのならし培地が切断型変異体をもはや切断できないプロテアーゼを含有していたかについての概略を示す。
我々は、通常使用されるヘパリン結合のモデル系を用いてマトリックス結合を解析した。我々は、BIAcoreを用いてヘパリン結合を解析した。予備的データは、K234A変異がヘパリン結合を5倍低減し(図8)、K180A、K181A変異がヘパリン結合に大きな効果を有することを示している。このデータは、おそらく2つのヘパリン結合部位がIGFBP−2にあることを示唆している。
本検定は、HT−29結腸直腸癌細胞が5mMブチレート中でアポトーシスに至ることを示している。IGF−Iの添加は、細胞をブチレート誘発アポトーシスから、投与量依存性の態様で救済する。IGFBP−2の増量は、細胞をブチレート誘発アポトーシスから救済するIGF−Iの能力を、IGFをIGF受容体から隔離することによって阻害する。変異体Des(114〜170)とDes(114〜170)K180A K181Aは、IGF−Iの作用の阻害においてより有効である。この分析は、Des(114〜170)とDes(114〜170)K180A K181Aとの間にほとんど差異がないことを示し、最大の利点が、プロテアーゼ切断部位の除去によってその分子に与えられる蛋白質加水分解への抵抗性であることを示唆している。K180AおよびK181Aの位置の変異によっても、さらなる蛋白質加水分解からの保護や細胞外マトリックスとの相互作用の阻害が可能となるだろう。しかし、この分析の条件下では、Des(114〜170)とDes(114〜170)K180A K181Aとの間に有意の差異を検出することは不可能である。
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Claims (16)
- 少なくともIGF1型受容体と同等の親和性でIGF−IまたはIGF−IIと結合することができる改変ヒトIGFBP−2分子であって、ヒトIGFBP−2分子における114−170のアミノ酸が欠失している点でヒトIGFBP−2分子とは異なるものである改変ヒトIGFBP−2分子。
- ヒトIGFBP−2分子における180、181、227、234、および237のうち1つまたは複数の位置にあるリシンが中性アミノ酸または酸性アミノ酸に置換されている、請求項1に記載の改変ヒトIGFBP−2分子。
- 180、181、227、234、および237のうち1つまたは複数の位置にあるリシンがアラニンに置換されている、請求項2に記載の改変ヒトIGFBP−2分子。
- 180および181の位置にあるリシンがアラニンに置換されている、請求項2に記載の改変ヒトIGFBP−2分子。
- 234の位置にあるリシンがアラニンに置換されている、請求項2に記載の改変ヒトIGFBP−2分子。
- 180、181および234の位置にあるリシンがアラニンに置換されている、請求項2に記載の改変ヒトIGFBP−2分子。
- 少なくともIGF1型受容体と同等の親和性でIGF−IまたはIGF−IIと結合することができる改変ヒトIGFBP−2分子をコードする、単離された核酸分子であって、前記改変ヒトIGFBP−2分子が、ヒトIGFBP−2分子における114−170のアミノ酸が欠失している点でヒトIGFBP−2分子とは異なるものである、核酸分子。
- 前記ヒトIGFBP−2分子における180、181、227、234、および237のうち1つまたは複数の位置にあるリシンが中性アミノ酸または酸性アミノ酸に置換されたものである、請求項7に記載の単離された核酸分子。
- 前記改変ヒトIGFBP−2分子が、180、181、227、234、および237のうち1つまたは複数の位置にあるリシンがアラニンに置換されたものである、請求項8に記載の単離された核酸分子。
- 前記改変ヒトIGFBP−2分子が、180および181の位置にあるリシンがアラニンに置換されたものである、請求項8に記載の単離された核酸分子。
- 前記改変ヒトIGFBP−2分子が、234の位置にあるリシンがアラニンに置換されたものである、請求項8に記載の単離された核酸分子。
- 前記改変ヒトIGFBP−2分子が、180、181および234の位置にあるリシンがアラニンに置換されたものである、請求項8に記載の単離された核酸分子。
- 請求項7〜請求項12のいずれか一項に記載の核酸分子を保持する宿主細胞。
- 癌性細胞集団のIGFに媒介された増殖を低減する方法であって、前記細胞集団を請求項1から6のいずれか一項に記載の改変ヒトIGFBP−2分子に接触させる工程を含む方法(ヒトに対する治療を除く)。
- 前記癌性細胞が前立腺、結腸および乳癌細胞からなる群から選択される、請求項14に記載の癌性細胞集団のIGFに媒介された増殖を低減する方法。
- 前記癌性細胞が結腸癌細胞である、請求項14に記載の癌性細胞集団のIGFに媒介された増殖を低減する方法。
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AU2001274536A1 (en) * | 2000-06-15 | 2002-01-02 | Kyowa Hakko Kogyo Co. Ltd. | Insulin-like growth factor-binding protein |
AU2002950188A0 (en) * | 2002-07-12 | 2002-09-12 | The University Of Adelaide | Altered insulin-like growth factor binding proteins |
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2002
- 2002-07-12 AU AU2002950188A patent/AU2002950188A0/en not_active Abandoned
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JP2006514535A (ja) | 2006-05-11 |
US7488798B2 (en) | 2009-02-10 |
CA2491917A1 (en) | 2004-01-22 |
AU2002950188A0 (en) | 2002-09-12 |
US20060153853A1 (en) | 2006-07-13 |
EP1534744A1 (en) | 2005-06-01 |
US20090075876A1 (en) | 2009-03-19 |
NZ537556A (en) | 2008-07-31 |
EP1534744A4 (en) | 2006-01-04 |
WO2004007543A1 (en) | 2004-01-22 |
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