Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence
Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence
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DOI：
10.1128/mcb.22.10.3389-3403.2002
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发表时间：
2002-05-01
影响因子：
5.3
通讯作者：
Sun, PQ
中科院分区：
文献类型：
--
作者：
Wang, WP;Chen, JX;Sun, PQ
在原代哺乳动物细胞中，致癌ras通过激活mek -细胞外信号调节激酶（ERK）、丝裂原活化蛋白激酶（MAPK）途径诱导过早衰老。目前还不清楚ras如何激活有丝分裂MEK-ERK通路来抑制生长。在这项研究中，我们发现应激激活的MAPK p38在ras诱导的人原代成纤维细胞衰老过程中也被激活。活性MKK3或MKK6对p38的组成性激活可诱导衰老。当p38活性被抑制时，致癌ras不能引起衰老，这表明p38的激活对于ras诱导的衰老是必不可少的。此外，我们已经证明，由于MEK-ERK通路被激活，p38活性受到ras的刺激。在MEK和ERK激活后，致癌ras的表达以MEK依赖的方式导致MKK3/6和p38活性的积累，并随后诱导衰老。活跃的MEK1诱导相同的一系列变化，并依赖于活跃的p38引发衰老。因此，在正常的原代细胞中，致癌ras通过顺序激活MEK-ERK和MKK3/6-p38通路来引发过早衰老。这些研究已经确定了ras信号级联中导致过早衰老的分子事件，从而为ras如何在原代细胞中引起致癌转化提供了新的见解。
In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.