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PML induces a novel caspase-independent death process
F Quignon1, F De Bels, M Koken
1CNRS 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.
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/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.
Insights
PML overexpression triggers rapid cell death independent of caspases, involving nuclear bodies (NBs). PML contributes to interferon-induced apoptosis, revealing a novel cell death pathway.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- PML nuclear bodies (NBs) are nuclear structures affected by viruses and oncogenes.
- PML protein's role in cell death and its association with interferon (IFN) signaling is not fully understood.
Purpose of the Study:
- To investigate the role of PML overexpression in inducing cell death.
- To identify novel proteins associated with PML nuclear bodies and their role in cell death.
- To explore the interaction between PML, interferon, and arsenic in regulating cell survival.
Main Methods:
- Overexpression of PML and analysis of cell death.
- Assessment of caspase activation and cell cycle.
- Immunofluorescence to track protein localization to nuclear bodies.
- Treatment with caspase inhibitors (zVAD) and arsenic.
Main Results:
- PML overexpression induces rapid cell death, independent of transcription and cell cycling, with cytoplasmic apoptotic features but no caspase-3 activation.
- Caspase inhibitors (zVAD) accelerate PML-induced death and enhance interferon (IFN)-induced death, suggesting PML's role in IFN-mediated apoptosis.
- BAX and p27KIP1 are novel NB-associated proteins recruited by PML, while the PML/RAR alpha oncoprotein delocalizes them.
- Arsenic enhances the recruitment of PML, BAX, and p27KIP1 to NBs, synergizing with PML and IFN to induce cell death.
Conclusions:
- A novel cell death pathway exists that is independent of caspase-3 activation, with PML nuclear bodies playing a role in controlling cell survival.
- Cell death susceptibility is linked to the recruitment of specific proteins to PML nuclear bodies.
- PML protein is a key regulator of a non-canonical cell death pathway and influences cellular response to interferon and arsenic treatment.