title: 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.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: K-S
authors.initials: KS
authors.lastname: Hsu
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: B-J
authors.initials: BJ
authors.lastname: Guan
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: D
authors.initials: D
authors.lastname: Guan
authors.affiliation: Department of Dermatology, University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lam
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hatzoglou
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.|The Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Kao
mesh_terms: D020121:5' Untranslated Regions; D017209:Apoptosis; D001943:Breast Neoplasms; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology*; D006801:Humans; D000067556:Internal Ribosome Entry Sites; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D000067556:Internal Ribosome Entry Sites; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C439524:TNF protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10