PML induces a novel caspase-independent death process

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.

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

“…In these cells, however, treatment with this peptide did not a ect the ability of DAPK2 to induce apoptosis (our unpublished data), suggesting that DAPK2-induced apotosis is independent of the caspase activation or DAPK2 functions downstream to the caspases. Recently, it has been reported that several types of apoptosis are not inhibited by the caspase inhibitors (Xiang et al, 1996;Miller et al, 1997;Lavoie et al, 1998;Quignon et al, 1998). DAPK2-induced cell death may contribute with these pathways.…”

Mechanisms of apoptosis by c-Myc

“…Emerging caspase-independent aspects of apoptosis (e.g. Quignon et al, 1998;Wang et al, 1998b) may give insights into the manner in which a death commitment signal is generated and into the exact relationship between c-Myc and mitochondrial events that are regulated by the Bcl-2 family.…”

Body language: the function of PML nuclear bodies in apoptosis regulation

“…PML also regulates a caspase-independent apoptosis pathway. 86 Using an inducible overexpression system, it has been shown that PML can trigger a death pathway independent from de novo protein synthesis that is not sensitive to synthetic caspase inhibitors. 86 However, this finding remains to be confirmed under more physiological conditions.…”

“…86 Using an inducible overexpression system, it has been shown that PML can trigger a death pathway independent from de novo protein synthesis that is not sensitive to synthetic caspase inhibitors. 86 However, this finding remains to be confirmed under more physiological conditions. An overview of currently known PML-NB-associated proteins and their function in cell surface receptor-mediated or nuclear apoptosis pathways are given in Table 1 and in Figure 2.…”