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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology*
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Caspases / physiology
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Ceramides / pharmacology
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DNA Damage
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Enzyme Activation
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Female
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Interferons / pharmacology
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Leukemia, Promyelocytic, Acute / etiology
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Leukemia, Promyelocytic, Acute / genetics
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Male
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Mice
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Mice, Knockout
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nuclear Proteins*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology
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Promyelocytic Leukemia Protein
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Suppressor Proteins
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fas Receptor / physiology
Substances
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Ceramides
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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fas Receptor
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Interferons
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Caspases