gp130シグナルによる赤血球、顆粒球、巨核球産生法の確立とその分子機構の解明

1997 Fiscal Year Annual Research Report

• Project/Area Number: 07407023
• Research Institution: The University of Tokyo
• Principal Investigator: 中畑 龍俊 東京大学, 医科学研究所, 教授 (20110744)
• Co-Investigator(Kenkyū-buntansha): 渡辺 すみ子 東京大学, 医科学研究所, 助手 (60240735) ; 辻 浩一郎 東京大学, 医科学研究所, 助教授 (50179991)
• Keywords: gp130 / c-kit / EPOR / 可溶性IL-6受容体(sIL-6R) / 赤芽球分化 / GATA-1 / STAT5 / HML

Research Abstract

IL-6と可溶性IL-6受容体(しL-6R)を用いてgp130を直接活性化する事により、stem cell factor(SCF)あるいはflk2/flt3 ligand存在下に、造血幹細胞から赤血球がEPO非存在下でも産生できることが確認された。EPO受容体(EPOR)とSCF存在下に見られるgp130の活性化による赤芽球や赤血球の産生は、抗体を用いた中和実験などにより全く独立のシステムであることが明らかとなった。われわれが最近樹立したヒト白血病細胞株HML-1細胞を用いても、gp130とcーkit受容体を活性化することにより赤芽球系への分化が見られた。赤芽球系細胞の増殖、分化、成熟において、両システムの細胞内シグナル伝達機構が同じであるのか、異なる細胞内シグナル伝達機構を使っても造血幹細胞から最終的に赤血球まで分化成熟させうるのか明らかにするため、赤芽球分化に関与するシグナル伝達分子、転写因子等について解析した。その結果SCFとgp130の同時活性化において赤芽球系遺伝子の発現に重要な転写因子GATA-1の発現がmRNAレベルで増強するが、それぞれ単独では増強しないこと、SCFはGATA-1非依存的にEPORの発現を促進し、限定的に極初期の赤芽球分化を誘導することを示唆する結果を得た。またEPO刺激によってリン酸化を受けることが知られているSTAT5についても、SCFとgp130の同時活性化で弱くリン酸化を受けることが認められた。以上より程度の差は有るがEPO及びSCFとgp130の同時刺激系の両方で、共通の転写因子・シグナル伝達分子が使用されることが示唆された。

Research Products

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