Apoptosis Department and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Oncogene. 2012 Jan 19;31(3):390-401. doi: 10.1038/onc.2011.230. Epub 2011 Jun 27.
Ras is one of the most frequently activated oncogenes in cancer. Two mitogen-activated protein kinases (MAPKs) are important for ras transformation: extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 2 (JNK2). Here we present a downstream signal amplification cascade that is critical for ras transformation in murine embryonic fibroblasts. This cascade is coordinated by ERK and JNK2 MAPKs, whose Ras-mediated activation leads to the enhanced levels of three oncogenic transcription factors, namely, c-Myc, activating transcription factor 2 (ATF2) and ATF3, all of which are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.
Ras 是癌症中最常被激活的致癌基因之一。两种丝裂原活化蛋白激酶（MAPKs）对于 ras 转化很重要：细胞外信号调节激酶（ERK）和 c-Jun N 端激酶 2（JNK2）。在这里，我们提出了一个下游信号放大级联反应，对于鼠胚胎成纤维细胞中的 ras 转化至关重要。这个级联反应由 ERK 和 JNK2 MAPKs 协调，其 Ras 介导的激活导致三种致癌转录因子（即 c-Myc、激活转录因子 2（ATF2）和 ATF3）的水平增强，所有这些转录因子对于 ras 转化都是必不可少的。先前的研究表明，ERK 介导的丝氨酸 62 磷酸化保护 c-Myc 免受蛋白酶体降解。然而，ERK 本身不足以稳定 c-Myc，但需要癌性蛋白磷酸酶 2A 抑制剂（CIP2A）的合作，CIP2A 是一种对抗蛋白磷酸酶 2A 介导的 c-Myc 去磷酸化的致癌基因。在这里，我们表明 JNK2 通过 ATF2 调节 Cip2a 转录。ATF2 和 c-Myc 合作激活 ATF3 的转录。值得注意的是，不仅异位 JNK2，而且异位 ATF2、CIP2A、c-Myc 和 ATF3 足以挽救 JNK2 缺陷细胞中缺陷的 ras 转化。因此，这些数据确定了 JNK2 和 ERK 途径的关键信号汇聚点，并强调了 CIP2A 在 ras 转化中的核心作用。
