PML induces a novel caspase-independent death process.
PML nuclear bodies (NBs) are nuclear matrix-associated structures altered by viruses and oncogenes. We show here that PML overexpression induces rapid cell death, independent of de novo transcription and cell cycling. PML death involves cytoplasmic features of apoptosis in the absence of caspase-3 activation, and caspase inhibitors such as zVAD accelerate PML death. zVAD also accelerates interferon (IFN)-induced death, suggesting that PML contributes to IFN-induced apoptosis. The death effector BAX and the cdk inhibitor p27KIP1 are novel NB-associated proteins recruited by PML to these nuclear domains, whereas the acute promyelocytic leukaemia (APL) PML/RAR alpha oncoprotein delocalizes them. Arsenic enhances targeting of PML, BAX and p27KIP1 to NBs and synergizes with PML and IFN to induce cell death. Thus, cell death susceptibility correlates with NB recruitment of NB proteins. These findings reveal a novel cell death pathway that neither requires nor induces caspase-3 activation, and suggest that NBs participate in the control of cell survival.
Quignon
F
F
CNRS UPR 9051, Laboratoire associé au comité de Paris de la ligue contre le cancer, Institut d'Hématologie de l'Université Paris VII, Hôpital St Louis, France.
De Bels
F
F
Koken
M
M
Feunteun
J
J
Ameisen
J C
JC
de Thé
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001151:Arsenic / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D011994:Recombinant Proteins; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494828:Bax protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D007370:Interferon Type I; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C070576:PML protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D001151:Arsenic