Translational control of PML contributes to TNF alpha-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs

摘要

The tumor suppressor protein promyelocytic leukemia (PML) is a key regulator of inflammatory responses and tumorigenesis and functions through the assembly of subnuclear structures known as PML nuclear bodies (NBs). The inflammation-related cytokine tumor necrosis factor-alpha (TNF alpha) is known to induce PML protein accumulation and PML NB formation that mediate TNF alpha-induced cell death in cancer cells and inhibition of migration and capillary tube formation in endothelial cells (ECs). In this study, we uncover a novel mechanism of PML gene regulation in which the p38 MAPK and its downstream kinase MAP kinase-activated protein kinase 1 (MNK1) mediate TNF alpha-induced PML protein accumulation and PML NB formation. The mechanism includes the presence of an internal ribosome entry site (IRES) found within the well-conserved 100 nucleotides upstream of the PML initiation codon. The activity of the PML IRES is induced by TNF alpha in a manner that involves MNK1 activation. It is proposed that the p38-MNK1-PML network regulates TNF alpha-induced apoptosis in breast cancer cells and TNF alpha-mediated inhibition of migration and capillary tube formation in ECs.