ONCOGENIC RAS ACTIVATES C-JUN VIA A SEPARATE PATHWAY FROM THE ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES
ONCOGENIC RAS ACTIVATES C-JUN VIA A SEPARATE PATHWAY FROM THE ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES
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DOI：
10.1073/pnas.91.13.6030
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发表时间：
1994-06-21
影响因子：
11.1
通讯作者：
BRENNER, DA
中科院分区：
文献类型：
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作者：
WESTWICK, JK;COX, AD;BRENNER, DA
c-Jun 转录活性通过致癌 Res 和 Raf 蛋白的表达而增强。这项研究表明 Ras 转化活性与 c-Jun 激活之间存在直接相关性，支持 c-Jun 在 Ras 转化中发挥重要作用。由于我们观察到 Ras 通过增加残基 Ser-63/Ser-73 处 c-Jun 激活结构域的磷酸化来激活 c-Jun 转录活性，并且致癌 Ras 蛋白激活细胞外信号调节蛋白激酶（ERK1 和 ERK2）（也称为丝裂原激活蛋白激酶），因此我们评估了 ERK 直接负责 c-Jun 激活的可能性。野生型 ERK 与致癌 Ras 蛋白的共表达增强，而激酶缺陷型 ERK 则抑制 Ras 诱导的来自 NVL-3 增强子中 Ras 响应元件 (Ets-1/AP-1) 和 c-fos 启动子中血清响应元件的转录激活。相反，野生型或激酶缺陷型 ERK 的共表达会抑制 c-Jun 转录活性的 Ras 和 Raf 激活。因此，虽然 ERK 和 c-Jun 的激活都是 Ras 信号转导途径激活的下游结果，但我们的结果表明 Ras 诱导的 c-Jun 磷酸化和转录激活并不是 ERK1 和 ERK2 激活的直接结果。
c-Jun transcriptional activity is augmented by expression of oncogenic Res and Raf proteins. This study demonstrates a direct correlation between Ras transforming activity and c-Jun activation, supporting an important role for c-Jun in transformation by Ras. Since we observed that Ras activated c-Jun transcriptional activity by increasing phosphorylation of the c-Jun activation domain at residues Ser-63/Ser-73 and that oncogenic Ras proteins activated extracellular signal-regulated protein kinases (ERK1 and ERK2) (also known as mitogen-activated protein kinases), we evaluated the possibility that ERKs were directly responsible for c-Jun activation. Coexpression of wild-type ERKs with oncogenic Ras proteins potentiated, while kinase-defective ERKs inhibited, Ras-induced transcriptional activation from the Ras-responsive element (Ets-1/AP-1) present in the NVL-3 enhancer and the serum-response element in the c-fos promoter. In contrast, coexpression of either wild-type or kinase-defective ERKs inhibited Ras and Raf activation of c-Jun transcriptional activity. Thus, although activation of both ERK and c-Jun are downstream consequences of activation of the Ras signal transduction pathway, our results suggest that Ras-induced c-Jun phosphorylation and transcriptional activation are not a direct consequence of ERK1 and ERK2 activation.