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Wang, ZG, Ruggero, D, Ronchetti, S, Zhong, S, Gaboli, M, Rivi, R and Pandolfi, PP (1998) PML is essential for multiple apoptotic pathways. Nat. Genet. 20:266-72
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.
Animals; Antigens, CD95/physiology; Apoptosis/drug effects; Apoptosis/genetics; Apoptosis/physiology; Caspases/physiology; Ceramides/pharmacology; DNA Damage; Enzyme Activation; Female; Interferons/pharmacology; Leukemia, Promyelocytic, Acute/etiology; Leukemia, Promyelocytic, Acute/genetics; Male; Mice; Mice, Knockout; Neoplasm Proteins/genetics; Neoplasm Proteins/physiology; Nuclear Proteins; Oncogene Proteins, Fusion/genetics; Oncogene Proteins, Fusion/physiology; Transcription Factors/genetics; Transcription Factors/physiology; Tumor Necrosis Factor-alpha/pharmacology; Tumor Suppressor Proteins
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