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

K. S. Hsu, B. J. Guan, X. Cheng, D. Guan, M. Lam, M. Hatzoglou, H. Y. Kao

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14 Citations (Scopus)

Abstract

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-α (TNFα) is known to induce PML protein accumulation and PML NB formation that mediate TNFα-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 TNFα-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 TNFα in a manner that involves MNK1 activation. It is proposed that the p38-MNK1-PML network regulates TNFα-induced apoptosis in breast cancer cells and TNFα-mediated inhibition of migration and capillary tube formation in ECs.

Original languageEnglish
Pages (from-to)469-483
Number of pages15
JournalCell Death and Differentiation
Volume23
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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