Abstract
Promyelocytic Leukemia (PML) is a nuclear protein that forms sub-nuclear structures termed nuclear bodies associated with transcriptionally active genomic regions. PML is a tumour suppressor and regulator of cell differentiation. We demonstrate that PML promotes TNFα-induced transcriptional responses by promoting NF-κB activity. TNFα-treated PML−/− cells show normal IκBα degradation and NF-κB nuclear translocation but significantly reduced NF-κB DNA binding and phosphorylation of NF-κB p65. We also demonstrate that the PML retinoic acid receptor-α (PML-RARα) oncofusion protein, which causes acute promyelocytic leukemia, inhibits TNFα induced gene expression and phosphorylation of NF-κB. This study establishes PML as an important regulator of NF-κB and demonstrates that PML-RARα dysregulates NF-κB.
Highlights
The promyelocytic leukaemia (PML) gene was originally identified at the t(15:17) translocation breakpoint characteristic of acute promyelocytic leukaemia (APL) which leads to the formation of a PML-retinoic acid receptor-alpha (RARα) fusion protein (PML-RARα)[1]
The PML-RARαenforced differentiation block in promyelocytes is reversed by treatment with all-trans retinoic acid (ATRA) or As2O3, both of which trigger the degradation of PML-RARαprotein and lead to the restoration of PML nuclear bodies[12]
Analysis revealed three distinct clusters of TNF-α-inducible genes which were reduced in PML−/− cells compared to wild type (WT) cells (Fig. 1A)
Summary
The promyelocytic leukaemia (PML) gene was originally identified at the t(15:17) translocation breakpoint characteristic of acute promyelocytic leukaemia (APL) which leads to the formation of a PML-retinoic acid receptor-alpha (RARα) fusion protein (PML-RARα)[1]. Studies using PML−/− mice have revealed PML as a tumour suppressor and regulator of retinoic acid-induced myeloid differentiation[6]. PML is required for TNFαand DNA damage induced activation of IKKεwhich in turn phosphorylates NF-κB p65 at S468 to modulate the expression of a subset of NF-κB target genes[8,9]. Whether this is sufficient to explain the role of PML in innate immunity is currently not clear. Our data shows that the oncofusion PML-RARαinhibits TNFα-induced expression of NF-κB target genes and blocks p65 phosphorylation. A bioinformatic analysis of APL transcriptomic datasets provides additional evidence for the suppression of NF-κB target genes by PML-RARα
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