PML is essential for multiple apoptotic pathways.
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.
Wang
Z G
ZG
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.
Ruggero
D
D
Ronchetti
S
S
Zhong
S
S
Gaboli
M
M
Rivi
R
R
Pandolfi
P P
PP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D002518:Ceramides / Q000494:pharmacology; D004249:DNA Damage; D004789:Enzyme Activation; D005260:Female; D007372:Interferons / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000502:physiology
D002518:Ceramides; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D007372:Interferons; D020169:Caspases