Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun
Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun
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DOI：
10.1038/sj.onc.1208064
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发表时间：
2004-09-30
期刊：
影响因子：
8
通讯作者：
Klempnauer, KH
中科院分区：
文献类型：
--
作者：
Bitomsky, N;Böhm, M;Klempnauer, KH
转化抑制基因Pdcd 4（programmed cell death gene 4）抑制肿瘤启动子介导的小鼠角质形成细胞转化，并且最近被认为是人肺癌发展中的潜在肿瘤抑制基因。生化分析表明，Pdcd 4蛋白参与蛋白质翻译以及核事件。最近的研究表明，Pdcd 4抑制AP-1响应启动子的反式激活的c-Jun，这表明Pdcd 4的转化抑制活性可能是由于，至少部分，抑制c-Jun活性。在这里，我们已经解决了Pdcd 4如何抑制c-Jun。我们表明，Pdcd 4干扰c-Jun的磷酸化的Jun N-末端激酶（JNK）。Pdcd 4对c-Jun磷酸化的抑制似乎不是由于JNK活性的一般抑制，我们的数据表明Pdcd 4与c-Jun相互作用，从而阻断c-Jun的磷酸化。除了影响c-Jun磷酸化外，Pdcd 4还阻断c-Jun对辅激活因子p300的募集。我们的结果有力地表明Pdcd 4直接参与c-Jun活性的调节。
The transformation suppressor gene Pdcd4 ( programmed cell death gene 4) inhibits the tumor-promoter mediated transformation of mouse keratinocytes and has recently been implicated as a potential tumor suppressor gene in the development of human lung cancer. Biochemical analysis has suggested that the Pdcd4 protein is involved in protein translation as well as in nuclear events. Recent work has shown that Pdcd4 suppresses the transactivation of AP-1 responsive promoters by c-Jun, suggesting that the transformation-suppressor activity of Pdcd4 might be due, at least in part, to the inhibition of c-Jun activity. Here, we have addressed how Pdcd4 inhibits c-Jun. We show that Pdcd4 interferes with the phosphorylation of c-Jun by Jun N-terminal kinase (JNK). The inhibition of c-Jun phosphorylation by Pdcd4 appears not to be due to a general suppression of JNK activity, our data rather suggest that Pdcd4 interacts with c-Jun and thereby blocks phosphorylation of c-Jun. In addition to affecting c-Jun phosphorylation, Pdcd4 blocks the recruitment of the coactivator p300 by c-Jun. Taken together, our results strongly suggest that Pdcd4 is directly involved in the regulation of c-Jun activity.