c-Abl-mediated tyrosine phosphorylation of JunB is required for Adriamycin-induced expression of p21.
c-Abl-mediated tyrosine phosphorylation of JunB is required for Adriamycin-induced expression of p21.
复制标题
阿霉素诱导的 p21 表达需要 c-Abl 介导的 JunB 酪氨酸磷酸化。
DOI：
10.1042/bj20150372
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发表时间：
2015
影响因子：
4.1
通讯作者：
and Naoto Yamaguchi.
中科院分区：
文献类型：
--
作者：
Noritaka Yamaguchi;Ryuzaburo Yuki;Sho Kubota;Kazumasa Aoyama;Takahisa Kuga;Yuuki Hashimoto;Takeshi Tomonaga;and Naoto Yamaguchi.
非受体型酪氨酸激酶 c-Abl 在细胞表面受体激活后充当细胞质信号转导器。 c-Abl 还参与 DDR（DNA 损伤反应），该反应在细胞核中启动，但其在 DDR 中的分子功能尚不完全清楚。在本研究中，我们发现 c-Abl 磷酸化 JunB，JunB 是 AP-1（激活蛋白 1）转录因子家族的成员。由于JunB被认为参与DDR，我们分析了c-Abl介导的JunB磷酸化在DDR中的作用。我们首先分析了JunB的磷酸化位点，发现c-Abl主要在Tyr173、Tyr182和Tyr188处磷酸化JunB。由于 c-Abl 在 DNA 损伤剂阿霉素（阿霉素）刺激下促进细胞周期蛋白依赖性激酶抑制剂 p21 的表达，因此我们分析了 JunB 在阿霉素诱导的 p21 表达中的参与情况。我们发现 JunB 通过抑制 p21 启动子活性来抑制 p21 诱导。磷酸化位点谷氨酸取代产生的拟磷酸化 JunB 未能抑制 p21 诱导。阿霉素刺激促进了 JunB 向 p21 启动子的募集，并通过与 c-Abl 抑制剂伊马替尼联合治疗进一步增强。 JunB 或阿霉素治疗中的拟磷谷氨酸取代损害了 JunB-c-Fos 转录因子复合物的形成。综上所述，这些结果表明，尽管 JunB 抑制 p21 启动子活性，但 c-Abl 使 JunB 磷酸化，并相反抑制其在阿霉素刺激下对 p21 启动子活性的抑制作用。因此，JunB 可能是阿霉素诱导的 DDR 中 p21 表达中 c-Abl 的关键靶标。
The non-receptor-type tyrosine kinase c-Abl functions as a cytoplasmic signal transducer upon activation of cell-surface receptors. c-Abl is also involved in DDR (DNA-damage response), which is initiated in the nucleus, whereas its molecular functions in DDR are not fully understood. In the present study, we found that c-Abl phosphorylates JunB, a member of the AP-1 (activator protein 1) transcription factor family. Because JunB was suggested to be involved in DDR, we analysed the role of c-Abl-mediated phosphorylation of JunB in DDR. We first analysed phosphorylation sites of JunB and found that c-Abl majorly phosphorylates JunB at Tyr173, Tyr182and Tyr188. Because c-Abl promotes expression of the cyclin-dependent kinase inhibitor p21 upon stimulation with the DNA-damaging agent Adriamycin (doxorubicin), we analysed the involvement of JunB in Adriamycin-induced p21 expression. We found that JunB suppresses p21 induction through inhibition of its promoter activity. The phosphomimetic JunB, which was generated by glutamic acid substitutions at the phosphorylation sites, failed to repress p21 induction. Recruitment of JunB to the p21 promoter was promoted by Adriamycin stimulation and was further enhanced by co-treatment with the c-Abl inhibitor imatinib. The phosphomimetic glutamic acid substitutions in JunB or Adriamycin treatment impaired the JunB–c-Fos transcription factor complex formation. Taken together, these results suggest that, although JunB represses p21 promoter activity, c-Abl phosphorylates JunB and conversely inhibits its suppressive role on p21 promoter activity upon Adriamycin stimulation. Therefore JunB is likely to be a key target of c-Abl in expression of p21 in Adriamycin-induced DDR.