EFFECTS OF RAS TRANSFORMATION ON THE INDUCTION OF THE IL-1 RECEPTOR-RELATED T1 GENE IN RESPONSE TO MITOGENS, ANISOMYCIN, IL-1 AND TNF-ALPHA

The T1 gene gives rise to two transcripts encoding a 62 kDa membrane-b ound 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 f ibroblasts and is strongly induced during the entry of quiescent cells into the cell cycle. Here we show that the T1 gene is also transcript ionally activated in response to the treatment of fibroblasts with cyc loheximide and anisomycin. These protein synthesis inhibitors are know n to stimulate the JNK and p38/RK signal transduction pathways. We pro vide evidence that anisomycin triggers T1 gene induction through the s timulation of the p38/RK MAP kinase. This observation is in line with our finding that physiological activators of the p38/RK pathway, the p roinflammatory cytokines IL-1 and TNF alpha, stimulate T1 gene express ion efficiently. Growth factor mediated T1 gene induction is a delayed early event, requiring ongoing protein synthesis. In contrast, anisom ycin induces T1 gene expression at concentrations which block translat ion completely. Thus, transcriptional induction of the T1 gene via the p38/RK pathway is an immediate early event not requiring de novo prot ein 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 p athway, IL-1, TNF alpha, and anisomycin led to strong T1 gene expressi on in normal and ras transformed NIH3T3 cells alike. Thus, the T1 gene can be induced through the activation of at least two MAP kinase path ways: signaling through the ERK pathway can occur in normal but not in ras transformed NIH3T3 cells, whereas the signaling through the p38/R K pathway is not affected by ras transformation.