A human suppressor of c-Jun N-terminal kinase 1 activation by tumor necrosis factor alpha
A human suppressor of c-Jun N-terminal kinase 1 activation by tumor necrosis factor alpha
复制标题
DOI：
10.1074/jbc.272.41.25816
复制
发表时间：
1997-10-10
影响因子：
4.8
通讯作者：
Jeang, KT
中科院分区：
文献类型：
--
作者：
Jin, DY;Teramoto, H;Jeang, KT
肿瘤坏死因子α（TNFα）对细胞代谢具有多效性作用。来自 TNF α 受体的信号传导途径之一会诱导应激激活的蛋白激酶级联反应。该 TNF α 激酶级联中的成分包括丝裂原激活蛋白激酶/细胞外信号调节激酶激酶激酶 1 (MEKK1) 和应激激活蛋白激酶/细胞外信号调节激酶激酶 (SEK)，它们调节 c-Jun N 末端激酶 1 (JNK1) 的活性。目前，将 TNF α 受体与下游激酶连接起来的 MEKK1 上游分子尚不清楚。除了 TNF α 之外，许多其他刺激物（包括几种癌蛋白）也可以激活 JNK1。在大多数情况下，从癌蛋白到 JNK1 的信号级联尚不清楚。我们在此报道人类 T 细胞淋巴病毒 I 型 (HTLV-I) 癌蛋白 Tax 可以激活 JNK1。我们通过结合 HTLV-I 癌蛋白的能力分离出一种新型人类细胞因子，G 蛋白通路抑制因子 2 (GPS2)，并且我们表明该因子可以有效抑制 JNK1 的 Tax 激活。在试图了解 GPS2 活性的机制时，我们发现它还抑制 TNF α 对 JNK1 的激活，但不能抑制 TNF α 对 p38 激酶的激活，也不能抑制佛波醇对细胞外信号调节激酶 2 的激活。由于 GPS2 对 MEKK1 或 SEK 调节的 JNK1 活性影响很小，因此它可以在此激酶级联的初始步骤中作用于 TNF α 受体和 MEKK1 之间的点。或者，不排除 GPS2 可以在从 TNF α 到 JNK1 的平行途径中发挥作用。 GPS2 代表了一种新分子，可以为细胞因子和癌蛋白介导的信号转导如何融合提供重要见解。
Tumor necrosis factor alpha (TNF alpha) has pleiotropic effects on cellular metabolism. One of the signaling paths from the TNF alpha receptor induces a stress-activated protein kinase cascade. Components within this TNF alpha kinase cascade include mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and stress-activated protein kinase/extracellular signal-regulated kinase kinase (SEK), which regulate the activity of c-Jun N-terminal kinase 1 (JNK1). Currently, molecules upstream of MEKK1 that link TNF alpha receptor to downstream kinases are not well understood. Besides TNF alpha, many other stimuli including several oncoproteins can activate JNK1. In most cases, the signaling cascade(s) leading from oncoproteins to JNK1 is poorly elucidated. We report here that the human T-cell lymphotrophic virus, type I (HTLV-I) oncoprotein, Tax, can activate JNK1. We isolated a novel human cell factor, G-protein pathway suppressor 2 (GPS2), by its ability to bind the HTLV-I oncoprotein, and we show that this factor can potently suppress Tax activation of JNK1. In trying to understand the mechanism of GPS2 activity, we found that it also suppressed TNF alpha activation of JNK1 but not TNF alpha activation of p38 kinase nor phorbol activation of extracellular signal-regulated kinase 2. Because GPS2 has minimal effect on MEKK1- or SEK-regulated JNK1 activity, it could act at a point between the TNF alpha receptor and MEKK1 in the initial step(s) of this kinase cascade. Alternatively, it is not excluded that GPS2 could work in a parallel pathway that leads from TNF alpha to JNK1. GPS2 represents a new molecule that could contribute important insights toward how cytokine-and oncoprotein-mediated signal transduction might converge.