title: Ectodomain shedding of TNF receptor 1 induced by protein synthesis inhibitors regulates TNF-alpha-mediated activation of NF-kappaB and caspase-8.
abstract: The transcription factor nuclear factor kappaB (NF-kappaB) plays a major role in the inducible resistance to death receptor-mediated apoptosis. It has been established that the protein synthesis inhibitor cycloheximide (CHX) sensitizes many types of cells to tumor necrosis factor (TNF)-alpha-induced apoptosis, mainly due to its ability to block de novo synthesis of cellular FLICE-inhibitory protein (c-FLIP). Nevertheless, we have surprisingly found that CHX, as well as its structural analogue acetoxycycloheximide (Ac-CHX), prevents TNF-alpha-mediated activation of NF-kappaB and caspase-8 in human lung carcinoma A549 cells. Both CHX and Ac-CHX reduced the expression of cell surface TNF receptor 1 (TNF-R1) in a dose-dependent manner, while Ac-CHX was approximately 100-fold more effective than CHX. Consistent with this observation, Ac-CHX induced the proteolytic cleavage of TNF-R1 and its release into the culture medium. CHX and Ac-CHX profoundly decreased constitutive and inducible expression of c-FLIP, whereas these compounds potentiated TNF-alpha-induced caspase-8 activation only when metalloprotease inhibitors were present. Thus, our results indicate that ectodomain shedding of TNF-R1 induced by protein synthesis inhibitors regulates TNF-alpha-mediated activation of NF-kappaB and caspase-8.
authors.affiliation: Center for Biological Resources and Informatics, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ogura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsukumo
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagai
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry* / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011500:Protein Synthesis Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003513:Cycloheximide; D053181:Caspase 8; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C004434:acetoxycycloheximide