Quignon F, De Bels F, Koken M, Feunteun J, Ameisen J C, de Thé H
CNRS UPR 9051, Laboratoire associé au comité de Paris de la ligue contre le cancer, Institut d'Hématologie de l'Université Paris VII, Hôpital St Louis, France.
Nat Genet. 1998 Nov;20(3):259-65. doi: 10.1038/3068.
PML nuclear bodies (NBs) are nuclear matrix-associated structures altered by viruses and oncogenes. We show here that PML overexpression induces rapid cell death, independent of de novo transcription and cell cycling. PML death involves cytoplasmic features of apoptosis in the absence of caspase-3 activation, and caspase inhibitors such as zVAD accelerate PML death. zVAD also accelerates interferon (IFN)-induced death, suggesting that PML contributes to IFN-induced apoptosis. The death effector BAX and the cdk inhibitor p27KIP1 are novel NB-associated proteins recruited by PML to these nuclear domains, whereas the acute promyelocytic leukaemia (APL) PML/RAR alpha oncoprotein delocalizes them. Arsenic enhances targeting of PML, BAX and p27KIP1 to NBs and synergizes with PML and IFN to induce cell death. Thus, cell death susceptibility correlates with NB recruitment of NB proteins. These findings reveal a novel cell death pathway that neither requires nor induces caspase-3 activation, and suggest that NBs participate in the control of cell survival.
早幼粒细胞白血病核小体（NBs）是与核基质相关的结构，会被病毒和癌基因改变。我们在此表明，早幼粒细胞白血病蛋白（PML）的过表达会诱导快速细胞死亡，这与从头转录和细胞周期无关。PML诱导的细胞死亡涉及在无半胱天冬酶-3激活情况下凋亡的细胞质特征，并且诸如zVAD之类的半胱天冬酶抑制剂会加速PML诱导的细胞死亡。zVAD还会加速干扰素（IFN）诱导的细胞死亡，这表明PML促成了IFN诱导的细胞凋亡。死亡效应蛋白BAX和细胞周期蛋白依赖性激酶抑制剂p27KIP1是由PML招募到这些核结构域的新型NB相关蛋白，而急性早幼粒细胞白血病（APL）的PML/RARα癌蛋白会使其发生异位。砷增强了PML、BAX和p27KIP1靶向NBs的能力，并与PML和IFN协同作用诱导细胞死亡。因此，细胞死亡易感性与NB相关蛋白向NBs的募集相关。这些发现揭示了一种既不需要也不诱导半胱天冬酶-3激活的新型细胞死亡途径，并表明NBs参与细胞存活的调控。
