title: Cytotrienin A, a translation inhibitor that induces ectodomain shedding of TNF receptor 1 via activation of ERK and p38 MAP kinase.
abstract: Cytotrienin A, a member of the triene-ansamycin family, was initially identified to be an inducer of apoptosis and recently shown to be an inhibitor of translation that interferes with eukaryotic elongation factor 1A function. In human lung carcinoma A549 cells, cytotrienin A was found to inhibit more strongly the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor (TNF)-α than the expression induced by interleukin (IL)-1α. Cytotrienin A induced the ectodomain shedding of TNF receptor 1 by TNF-α-converting enzyme (TACE). The TACE inhibitor TAPI-2 antagonized the selective inhibitory effect of cytotrienin A on inhibitor of nuclear factor-κB-α (IκBα) degradation as well as ICAM-1 expression in TNF-α-stimulated cells. The MEK inhibitor U0126 and the p38 MAP kinase inhibitor SB203580, but not the JNK inhibitor SP600125, prevented the ectodomain shedding of TNF receptor 1 induced by cytotrienin A and reversed the inhibitory effects of cytotrienin A on the TNF-α-induced IκBα degradation. In the presence of both U0126 and SB203580, cytotrienin A inhibited TNF-α- and IL-1α-induced ICAM-1 expression at almost equivalent concentrations. Thus, our present results demonstrate that cytotrienin A is a translation inhibitor that triggers ribotoxic stress response and selectively inhibits the TNF-α-induced ICAM-1 expression by inducing the ectodomain shedding of TNF receptor 1 via the activation of ERK and p38 MAP kinase.
authors.affiliation: Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism*; D012294:Rifamycins / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D012294:Rifamycins; D014409:Tumor Necrosis Factor-alpha; C106761:cytotrienin A; D018799:Intercellular Adhesion Molecule-1; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human