Laursen N B, Kessler R, Fröhli E, Klemenz R
Department of Pathology, University Hospital of Zurich, Switzerland.
Oncogene. 1998 Feb 5;16(5):575-86. doi: 10.1038/sj.onc.1201522.
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.
T1基因产生两种转录本，编码一种62 kDa的膜结合蛋白和一种37 kDa的分泌蛋白，它们与I型白细胞介素-1受体相似。它在增殖的成纤维细胞中弱表达，而在静止的成纤维细胞中不表达，并且在静止细胞进入细胞周期时被强烈诱导。在这里，我们表明，用环己酰亚胺和茴香霉素处理成纤维细胞后，T1基因也会被转录激活。已知这些蛋白质合成抑制剂会刺激JNK和p38/RK信号转导途径。我们提供的证据表明，茴香霉素通过刺激p38/RK丝裂原活化蛋白激酶触发T1基因诱导。这一观察结果与我们的发现一致，即p38/RK途径的生理激活剂促炎细胞因子IL-1和TNFα能有效刺激T1基因表达。生长因子介导的T1基因诱导是一个延迟的早期事件，需要持续的蛋白质合成。相比之下，茴香霉素在完全阻断翻译的浓度下诱导T1基因表达。因此，通过p38/RK途径对T1基因的转录诱导是一个即时早期事件，不需要从头合成蛋白质。T1基因在静止的NIH3T3成纤维细胞中被各种有丝分裂原强烈诱导，但在ras转化的NIH3T3细胞中则不然。相比之下，所有三种激活p38/RK途径的试剂IL-1、TNFα和茴香霉素在正常和ras转化的NIH3T3细胞中均能导致强烈的T1基因表达。因此，T1基因可以通过激活至少两条丝裂原活化蛋白激酶途径来诱导：通过ERK途径的信号传导可以在正常的NIH3T3细胞中发生，但在ras转化的NIH3T3细胞中则不能，而通过p38/RK途径的信号传导不受ras转化的影响。
