Pml is essential for multiple apoptotic pathways
Pml is essential for multiple apoptotic pathways
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DOI：
10.1038/3073
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发表时间：
1998-11-01
期刊：
影响因子：
30.8
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
--
作者：
Wang, ZG;Ruggero, D;Pandolfi, PP
急性早幼粒细胞白血病（APL）的PML基因编码细胞生长和肿瘤抑制因子，然而，PML抑制肿瘤发生的机制知之甚少。我们在这里表明，Pml是必需的Fas和caspase依赖的DNA损伤诱导的细胞凋亡。我们还发现，Pml是必不可少的诱导程序性细胞死亡的Fas，肿瘤坏死因子（TNF），神经酰胺和I型和II型干扰素（IFN）。因此，Pml（-/-）小鼠和细胞免受电离辐射和抗Fas抗体的致死作用。暴露于这些刺激物时，Pml是半胱天冬酶1和半胱天冬酶3激活所必需的。APL的PML-RAR α融合蛋白使造血祖细胞对Fas-、TNF-和IFN-诱导的凋亡具有抗性，缺乏半胱天冬酶3活化，因此充当Pml显性阴性产物。这些结果表明，Pml是多种凋亡信号的介导者，并且在APL的发病机制中涉及凋亡抑制。
The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage-induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor a (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml(-/-) mice and cells are protected from the lethal effects of ionizing radiation and anti-fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RAR alpha fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.