ONCOGENIC AND TRANSCRIPTIONAL COOPERATION WITH HA-RAS REQUIRES PHOSPHORYLATION OF C-JUN ON SERINE-63 AND SERINE-73
ONCOGENIC AND TRANSCRIPTIONAL COOPERATION WITH HA-RAS REQUIRES PHOSPHORYLATION OF C-JUN ON SERINE-63 AND SERINE-73
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DOI：
10.1038/354494a0
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发表时间：
1991-12-12
期刊：
影响因子：
64.8
通讯作者：
KARIN, M
中科院分区：
文献类型：
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作者：
SMEAL, T;BINETRUY, B;KARIN, M
最近的进展表明肿瘤启动子、转化和 AP-1 活性之间存在联系 1。蛋白激酶 C 激活可增加 AP-1 DNA 结合活性，独立于新蛋白质合成 2,3。 AP-1 也受到转化癌蛋白和生长因子 4-6 的刺激。这些蛋白被认为参与影响由 Jun 和 Fos 蛋白 1,7,8 组成的核 AP-1 复合物的信号级联。由于 c-Jun 是 AP-1 复合物 9-12 中最有效的反式激活因子，并且在 Ha-ras 转化细胞中升高，其中 c-Fos 下调 13,14，因此我们将其作为潜在靶点。 c-Jun 可以将致癌信号级联的输入转化为基因表达的变化。事实上，c-Jun 转化大鼠胚胎成纤维细胞需要完整的转录激活结构域 15 并与致癌 Ha-ras 16 配合。致癌 Ha-ras 的表达增强了 c-Jun 的反式激活并刺激其磷酸化 14。在这里，我们描述了 Ha-ras 响应性磷酸化位点与 c-Jun 丝氨酸 63 和 73 的映射。定点诱变表明这些丝氨酸的磷酸化对于刺激 c-Jun 活性以及与 Ha-ras 在基因转化中的合作至关重要。
RECENT advances indicate a link between tumour promoters, transformation, and AP-1 activity 1. Protein kinase C activation increases AP-1 DNA-binding activity independently of new protein synthesis 2,3. AP-1 is also stimulated by transforming oncoproteins and growth factors 4-6. These proteins are thought to participate in a signalling cascade affecting the nuclear AP-1 complex composed of the Jun and Fos proteins 1,7,8. Because c-Jun is the most potent transactivator in the AP-1 complex 9-12 and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated 13,14, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression. Indeed, transformation of rat embryo fibroblasts by c-Jun requires an intact transcriptional activation domain 15 and cooperation with oncogenic Ha-ras 16. Expression of oncogenic Ha-ras augments transactivation by c-Jun and stimulates its phosphorylation 14. Here we describe the mapping of the Ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-Jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-Jun activity and for cooperation with Ha-ras in ocogenic transformation.