Pml is essential for multiple apoptotic pathways

Abstract

The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage-induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor alpha (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml-/- mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RAR alpha fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.

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

“…[81][82][83] PML-NB components in receptormediated apoptosis pathways PML Cells derived from PMLÀ/À mice show, in addition to defects in ceramide-induced, g-irradiation-induced and type I and type II interferon-induced apoptosis, a strongly decreased sensitivity against death receptor-mediated apoptosis through stimulation with CD95L and TNF-a. 21 Moreover, injection of CD95-activating antibodies in PMLÀ/À mice resulted in a markedly decreased apoptosis-derived liver failure and increased survival time. Despite the defects in multiple apoptosis pathways, PMLÀ/À mice are viable and show no obvious abnormalities.…”

“…Despite the defects in multiple apoptosis pathways, PMLÀ/À mice are viable and show no obvious abnormalities. 21 This might reflect the particular importance of PML in apoptosis pathways that are not essential for normal development, reminiscent of the phenotype of the tumour suppressor p53, which also plays a pivotal role only in stress-induced apoptosis pathways. 84 Although a role of PML in death receptor-induced apoptosis is likely, there is currently no evidence that PML exerts a direct function in death receptor signalling by participating in receptor proximal events.…”

“…61,65,66 Although the DISC components and caspase-1, -3 and -8 are properly expressed, caspase activation is markedly inhibited upon CD95L or TNF-a stimulation in PML-deficient cells. 21 The underlying molecular defect explaining this interesting phenotype is presently unknown. Currently available evidence does not fully exclude the fact that nucleoplasmic or cytoplasmic PML can also directly regulate the apoptotic machinery NB-independently.…”

“…Although the molecular function of PMLNBs is currently not clear, there is accumulating evidence that PML-NBs are regulatory domains involved in various biological processes, including protein degradation, 5 transcriptional regulation, 8,9 cell growth, 10,11 antiviral response, 12,13 cellular senescence, [14][15][16][17] tumour suppression, 18 DNA repair 19,20 and apoptosis. [21][22][23][24][25] However, how can one explain that so many different and unrelated processes are linked to these nuclear domains? Since PML-NBs contain several dozens of functionally different residents (Figure 1), the current model is that PML-NBs play an important role in the regulation of these processes by controlling the function of its residents by altering their post-translational modification pattern and regulating their subcellular distribution.…”

The promyelocytic leukemia protein PML interacts with the proline-rich homeodomain protein PRH: a RING may link hematopoiesis and growth control

“…Hence, the nuclear organelle which PML forms, PML nuclear bodies, are disrupted forming a microparticulate pattern in the nucleus and cytoplasm. Pro-apoptotic and growth suppressive functions were attributed to PML and may be linked to the integrity of these bodies (Wang et al, 1998;Quignon et al, 1998;Borden et al, 1997;Rogaia et al, 1995;Ferrucci et al, 1997;Mu et al, 1994).…”