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PML induces a novel caspase-independent death process

Nature Genetics volume 20, pages 259–265 (1998)Cite this article

A Correction to this article was published on 01 May 1999

Abstract

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/RARα 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.

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Figure 1: PML induces cell death.
Figure 2: PML-triggered death is not associated with caspase activation.
Figure 3: IFN induces zVAD-accelerated cell death.
Figure 4: BAX and p27KIP are NB antigens.
Figure 5: A model for a pivotal role of PML in cell death (ref. 40 and this paper).

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Acknowledgements

We thank all members of the PML group for helpful suggestions, continuous support and critical reading of the manuscript. We also thank F. Puvion and E. Puvion for electronic microscopy work. The LPH is gratefully acknowledged for its artwork. We thank P.P. Pandolfi for exchanging manuscripts before publication. This project was supported by the CNRS, Ligue contre le Cancer (nationale and comité de Paris), ARC and EEC to H.d.T.; ANRS, FRM and INSERM to J.C.A.; the University of Paris VII and the Assistance Publique to both. F.Q. was supported by ARC and FRM.

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Authors and Affiliations

  1. 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, 1 av. C. Vellefaux, Paris, 75475, Cedex 10, France

    Frédérique Quignon, Marcel Koken & Hugues de Thé

  2. INSERM CJF 9707, Hôpital Bichat, 170 Bld Ney, Paris, 75877, Cedex 18, France

    Frédéric De Bels & Jean-Claude Ameisen

  3. CNRS URA 1967, Institut G. Roussy, 39 rue C. Desmoulins, Villejuif Cedex, 94805, France

    Jean Feunteun

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  1. Frédérique Quignon
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  2. Frédéric De Bels
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Correspondence to Jean-Claude Ameisen or Hugues de Thé.

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Quignon, F., De Bels, F., Koken, M. et al. PML induces a novel caspase-independent death process. Nat Genet 20, 259–265 (1998). https://doi.org/10.1038/3068

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