臨床薬理の進歩 No.43

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)nucnVXA2Hγ(egnahCdoF)nucnV35pegnahCdoF)nucnV35p-p(egnahCdoF)nucnVD1MPPegnahCdoFilililili/(l50)ni/(l43210i/l50ni/l8642018180185i/ll0i/l01818010)i/lli/l0atoT(ilil)n)nililucnVXA2Hγ(egnahCdoFucnV35pegnahCdoFucnV35p-p(egnahCdoFucnVD1MPPegnahCdoFatoT(γH2AX24hrs Combo8hrs Combo8hrs MAF0hrs MAF1hrs PPM1Di0hrs Combo24hrs MAF24hrs PPM1Di1hrs Combo0hrs PPM1Di1hrs MAF8hrs PPM1Di24hrs Combo8hrs Combo8hrs MAF0hrs MAF1hrs PPM1Di0hrs Combo24hrs MAF24hrs PPM1Di1hrs Combo0hrs PPM1Di1hrs MAF8hrs PPM1Di24hrs Combo8hrs Combo8hrs MAF0hrs MAF1hrs PPM1Di0hrs Combo24hrs MAF24hrs PPM1Di1hrs Combo0hrs PPM1Di1hrs MAF8hrs PPM1Di24hrs Combo8hrs Combo8hrs MAF0hrs MAF1hrs PPM1Di0hrs Combo24hrs MAF24hrs PPM1Di1hrs Combo0hrs PPM1Di1hrs MAF8hrs PPM1Di図3　PPM1D阻害によるマホスファミドのDNA損傷効果の増強PPM1D阻害剤とマホスファミドで処理したB細胞性ALL細胞株（RCH細胞）におけるTP53のリン酸化とDNA損傷マーカー（γH2AX）についてのウェスタンブロッティング。下図はこれらの結果を棒グラフにしたもの。γH2AX24hrs Combo8hrs Combo1hrs PPM1Di0hrs Combo24hrs PPM1Di1hrs Combo0hrs PPM1Di8hrs PPM1Di8hrs VCR0hrs VCR24hrs VCR1hrs VCR24hrs Combo8hrs Combo1hrs PPM1Di0hrs Combo24hrs PPM1Di1hrs Combo0hrs PPM1Di8hrs PPM1Di8hrs VCR0hrs VCR24hrs VCR1hrs VCR24hrs Combo8hrs Combo1hrs PPM1Di0hrs Combo0hrs VCR24hrs PPM1Di8hrs VCR24hrs VCR1hrs Combo0hrs PPM1Di8hrs PPM1Di1hrs VCR24hrs Combo8hrs Combo1hrs PPM1Di0hrs Combo0hrs VCR24hrs PPM1Di8hrs VCR24hrs VCR1hrs Combo0hrs PPM1Di8hrs PPM1Di1hrs VCR図4　PPM1D阻害によるビンクリスチンのDNA損傷効果の増強PPM1D阻害剤とビンクリスチンで処理したB細胞性ALL細胞株（RCH細胞）におけるTP53のリン酸化とDNA損傷マーカー（γH2AX）についてのウェスタンブロッティング。下図はこれらの結果を棒グラフにしたもの。されるSer/Thrホスファターゼである。PPM1Dを含むPPMホスファターゼは、Mg2+やMn2+の金属イオンをその酵素活性発現に必要とし、金属イオンに配位した水分子が求核分子として作用することにより基質タンパク質からの脱リン酸化を触媒するとされる8）。PPM1Dが関与する細胞のがん化2121151075 kDa50 kDa50 kDa15 kDa100 kDaPPMID75 kDa50 kDa50 kDa15 kDa100 kDaPPMID20151024Phospho-p53 (Ser15)24Phospho-p53 (Ser15)PPM1Di 50μM024MAF 1.5μMPPM1Di = GSK2830371PPM1Di 50μM024VCR 2 nM8PPM1Di = GSK283037115102.52.01.51.00.50.0MAF + PPM1Di024VCR + PPM1Di24Total p53Total p53PPM1D/WIP1Phospho-p53 (Ser15)p53γH2AXVinculinhrsPPM1D/WIP1Phospho-p53 (Ser15)p53γH2AXVinculin60402040302010