Regulation of NF-κB by PML and PML-RARα

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 TNF alpha-induced transcriptional responses by promoting NF-kappa B activity. TNF alpha-treated PML-/- cells show normal I kappa B alpha degradation and NF-kappa B nuclear translocation but significantly reduced NF-kappa B DNA binding and phosphorylation of NF-kappa B p65. We also demonstrate that the PML retinoic acid receptor-alpha (PML-RAR alpha) oncofusion protein, which causes acute promyelocytic leukemia, inhibits TNF alpha induced gene expression and phosphorylation of NF-kappa B. This study establishes PML as an important regulator of NF-kappa B and demonstrates that PML-RAR alpha dysregulates NF-kappa B.