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PML is essential for multiple apoptotic pathways.

Z G Wang·D Ruggero·S Ronchetti·S Zhong·M Gaboli·R Rivi·P P Pandolfi
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Abstract

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.

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AnimalsApoptosisCaspasesCeramidesDNA DamageEnzyme ActivationFemaleInterferonsLeukemia, Promyelocytic, AcuteMaleMiceMice, KnockoutNeoplasm ProteinsNuclear ProteinsOncogene Proteins, FusionPromyelocytic Leukemia ProteinTranscription FactorsTumor Necrosis Factor-alphaTumor Suppressor Proteinsfas ReceptorJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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Z G Wang, D Ruggero, S Ronchetti, S Zhong, M Gaboli, R Rivi, P P Pandolfi. 1998. PML is essential for multiple apoptotic pathways.. https://doi.org/10.1038/3073

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