title: Effects of ras transformation on the induction of the IL-1 receptor related T1 gene in response to mitogens, anisomycin, IL-1 and TNFalpha.
abstract: The T1 gene gives rise to two transcripts encoding a 62 kDa membrane-bound and a 37 kDa secreted protein with similarity to the type I IL-1 receptor. It is weakly expressed in proliferating but not in resting fibroblasts and is strongly induced during the entry of quiescent cells into the cell cycle. Here we show that the T1 gene is also transcriptionally activated in response to the treatment of fibroblasts with cycloheximide and anisomycin. These protein synthesis inhibitors are known to stimulate the JNK and p38/RK signal transduction pathways. We provide evidence that anisomycin triggers T1 gene induction through the stimulation of the p38/RK MAP kinase. This observation is in line with our finding that physiological activators of the p38/RK pathway, the proinflammatory cytokines IL-1 and TNFalpha, stimulate T1 gene expression efficiently. Growth factor mediated T1 gene induction is a delayed early event, requiring ongoing protein synthesis. In contrast, anisomycin induces T1 gene expression at concentrations which block translation completely. Thus, transcriptional induction of the T1 gene via the p38/RK pathway is an immediate early event not requiring de novo protein synthesis. The T1 gene is strongly induced by various mitogens in quiescent NIH3T3 fibroblasts but not in ras transformed NIH3T3 cells. In contrast, all of the three tested agent which activate the p38/RK pathway, IL-1, TNFalpha, and anisomycin led to strong T1 gene expression in normal and ras transformed NIH3T3 cells alike. Thus, the T1 gene can be induced through the activation of at least two MAP kinase pathways: signaling through the ERK pathway can occcur in normal but not in ras transformed NIH3T3 cells, whereas the signaling through the p38/RK pathway is not affected by ras transformation.
authors.affiliation: Department of Pathology, University Hospital of Zurich, Switzerland.
authors.forename: N B
authors.initials: NB
authors.lastname: Laursen
authors.forename: R
authors.initials: R
authors.lastname: Kessler
authors.forename: E
authors.initials: E
authors.lastname: Fröhli
authors.forename: R
authors.initials: R
authors.lastname: Klemenz
mesh_terms: D016475:3T3 Cells / Q000502:physiology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D011905:Genes, ras / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D015533:Transcriptional Activation / Q000187:drug effects; D014170:Transformation, Genetic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D008934:Mitogens; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000841:Anisomycin; D003513:Cycloheximide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580