Wang Z G, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi P P
Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
Nat Genet. 1998 Nov;20(3):266-72. doi: 10.1038/3073.
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 alpha (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.
急性早幼粒细胞白血病（APL）的PML基因编码一种细胞生长和肿瘤抑制因子，然而，PML抑制肿瘤发生的机制尚不清楚。我们在此表明，Pml是Fas和半胱天冬酶依赖性DNA损伤诱导的细胞凋亡所必需的。我们还发现，Pml对于Fas、肿瘤坏死因子α（TNF）、神经酰胺以及I型和II型干扰素（IFN）诱导的程序性细胞死亡至关重要。因此，Pml-/-小鼠和细胞对电离辐射和抗Fas抗体的致死作用具有抗性。暴露于这些刺激时，Pml是半胱天冬酶1和半胱天冬酶3激活所必需的。APL的PML-RARα融合蛋白使造血祖细胞对Fas、TNF和IFN诱导的细胞凋亡具有抗性，且缺乏半胱天冬酶3激活，因此作为一种Pml显性负性产物发挥作用。这些结果表明，Pml是多种凋亡信号的介导因子，并提示细胞凋亡抑制在APL发病机制中起作用。
