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Induction of the PML protein by interferons in normal and APL cells
M K Chelbi-Alix1, L Pelicano, F Quignon
1CNRS UPR 43, Paris, France.
Abstract:
PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia (APL). The PML protein is specifically associated to nuclear bodies (NBs) whose alterations in APL were proposed to contribute to leukemogenesis. The role of this nuclear domain (which also harbors the Sp100 autoantigen and the NDP52 protein) is unknown. Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells. Interestingly, the NBs that contain the three IFN-induced proteins appear to be associated to speckles labelled by the IFN-mediator Mx1. These observations link NBs to IFN response pathways, which may contribute to the elucidation of the biological role of these structures. In APL cells, IFNs induced both PML and PML/RAR alpha expression, resulting in an increased sequestration of PML and RXRs in the microspeckles induced by the fusion protein. As PML has growth suppressing properties, it may mediate some of the antiproliferative effects of IFN. In APL, inactivation of PML may result in disruption of growth control.
Insights
Interferons (IFNs) induce PML protein, a key factor in acute promyelocytic leukemia (APL). This links nuclear bodies to IFN responses and suggests PML
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The PML protein is implicated in acute promyelocytic leukemia (APL) through its fusion to the RAR alpha gene.
- Alterations in PML-associated nuclear bodies (NBs) are proposed to contribute to APL leukemogenesis.
- The precise function of NBs, which contain Sp100 and NDP52, remains largely unknown.
Purpose of the Study:
- To investigate the role of PML protein and its associated nuclear bodies (NBs) in cellular responses.
- To explore the relationship between NBs and interferon (IFN) signaling pathways.
- To understand the impact of IFNs on PML expression and function in both normal and APL cells.
Main Methods:
- Induction of PML, Sp100, and NDP52 proteins by interferons (IFNs alpha, beta, gamma) in various human cell types.
- Microscopic analysis to observe the association of NBs with IFN-induced speckles (Mx1).
- Assessment of PML and PML/RAR alpha expression and nuclear body sequestration in APL cells treated with IFNs.
Main Results:
- PML, Sp100, and NDP52 proteins are induced by IFNs across diverse human cells.
- IFN-induced NBs colocalize with speckles labeled by the IFN-mediator Mx1.
- In APL cells, IFNs increase PML and PML/RAR alpha expression, leading to enhanced sequestration of PML and RXRs within microspeckles.
Conclusions:
- NBs are linked to IFN response pathways, offering insights into their biological functions.
- IFN-induced PML may mediate antiproliferative effects, potentially through its growth-suppressing properties.
- In APL, the inactivation of PML might disrupt cellular growth control mechanisms.