Pml is essential for multiple apoptotic pathways

• Published in: Nature genetics Vol. 20; no. 3; pp. 266 - 272
• Main Authors: Pandolfi, Pier Paolo, Wang, Zhu-Gang, Ruggero, Davide, Ronchetti, Simona, Zhong, Sue, Gaboli, Mirella, Rivi, Roberta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-11-1998
• Subjects: Ageing, cell death; Animals; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Biological and medical sciences; Caspases - physiology; Cell physiology; Ceramides - pharmacology; DNA Damage; Enzyme Activation; fas Receptor - physiology; Female; Fundamental and applied biological sciences. Psychology; Interferons - pharmacology; Leukemia, Promyelocytic, Acute - etiology; Leukemia, Promyelocytic, Acute - genetics; Male; Mice; Mice, Knockout; Molecular and cellular biology; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Nuclear Proteins; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - physiology; Promyelocytic Leukemia Protein; Transcription Factors - genetics; Transcription Factors - physiology; Tumor Necrosis Factor-alpha - pharmacology; Tumor Suppressor Proteins; Promyelocytic leukemia; Animal model; Nucleoskeleton; Acute; Rodentia; Cytokine; Malignant hemopathy; Carcinogenesis; Signal transduction; Vertebrata; Regulation(control); Mammalia; Mouse; Mutation; Nuclear protein; Apoptosis; Tumor suppressor gene
• ISSN: 1061-4036; 1546-1718
• 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.