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

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.

• Authors: K-S Hsu, B-J Guan, X Cheng, D Guan, M Lam, M Hatzoglou, H-Y Kao
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 23 Issue 3 Pg. 469-83 (Mar 2016) ISSN: 1476-5403 [Electronic] England
• PMID: 26383972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 5' Untranslated Regions
• CCL2 protein, human
• Chemokine CCL2
• Internal Ribosome Entry Sites
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• Promyelocytic Leukemia Protein
• TNF protein, human
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Proteins
• PML protein, human
• MKNK1 protein, human
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• MMP10 protein, human
• Matrix Metalloproteinase 10

Topics

• 5' Untranslated Regions
• Apoptosis
• Breast Neoplasms
• Cell Movement
• Cell Proliferation
• Chemokine CCL2 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• HL-60 Cells
• Human Umbilical Vein Endothelial Cells (physiology)
• Humans
• Internal Ribosome Entry Sites
• Intracellular Signaling Peptides and Proteins (metabolism)
• MCF-7 Cells
• Matrix Metalloproteinase 10 (genetics, metabolism)
• Neovascularization, Physiologic
• Nuclear Proteins (genetics, metabolism)
• Promyelocytic Leukemia Protein
• Protein Biosynthesis
• Protein Serine-Threonine Kinases (metabolism)
• Transcription Factors (genetics, metabolism)
• Tumor Necrosis Factor-alpha (physiology)
• Tumor Suppressor Proteins (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)