PML INDUCES A NOVEL CASPASE-INDEPENDENT DEATH PROCESS

PML nuclear bodies (NBs) are nuclear matrix-associated structures alte red by viruses and oncogenes. We show here that PML overexpression ind uces rapid cell death, independent of de novo transcription and cell c ycling. PML death involves cytoplasmic features of apoptosis in the ab sence of caspase-3 activation, and caspase inhibitors such as zVAD acc elerate PML death, zVAD also accelerates interferon (IFN)-induced deat h, suggesting that PML contributes to IFN-induced apoptosis. The death effector BAX and the cdk inhibitor p27KIP1 are novel NB-associated pr oteins recruited by PML to these nuclear domains, whereas the acute pr omyelocytic leukaemia (APL) PML/RAR alpha oncoprotein delocalizes them . Arsenic enhances targeting of PML BAX and p27KIP1 to NBs and synergi zes with PML and IFN to induce cell death. Thus, cell death susceptibi lity correlates with NE recruitment of NE proteins. These findings rev eal a novel cell death pathway that neither requires nor induces caspa se-3 activation, and suggest that NBs participate in the control of ce ll survival.