Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway
Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway
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DOI：
10.1038/sj.onc.1210526
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发表时间：
2007-11-08
期刊：
影响因子：
8
通讯作者：
Krupenko, S. A.
中科院分区：
文献类型：
--
作者：
Oleinik, N. V.;Krupenko, N. I.;Krupenko, S. A.
FDH（10-甲酰基四氢叶酸脱氢酶）在肿瘤中被强烈下调，其升高抑制癌细胞的增殖并诱导p53依赖性细胞凋亡。我们之前已经证明，FDH诱导p53的Ser6位点磷酸化，这是激活细胞凋亡的必要步骤。在本研究中，我们报道了fdh诱导的p53磷酸化是由JNK1和JNK2 （c-Jun n末端激酶）协同作用进行的。我们已经证明，FDH诱导JNK1和JNK2的磷酸化，而用JNK抑制剂SP600125处理表达FDH的细胞，以及用siRNA敲低JNK1或JNK2，可以阻止p53的Ser6位点磷酸化，并保护细胞免于凋亡。有趣的是，在FDH的作用下，JNK1的敲低会消除JNK2的磷酸化，而JNK2的敲低并不会阻止JNK1的磷酸化。p53特异性抗体的下拉实验表明，JNK2而不是JNK1与p53存在物理关联。我们的研究揭示了一种新的机制，即JNK1介导JNK2的磷酸化，然后p53被JNK2在Ser6位点直接磷酸化。
FDH (10-formyltetrahydrofolate dehydrogenase) is strongly downregulated in tumors while its elevation suppresses proliferation of cancer cells and induces p53-dependent apoptosis. We have previously shown that FDH induces phosphorylation of p53 at Ser6, which is a required step in the activation of apoptosis. In the present study, we report that FDH-induced p53 phosphorylation is carried out by JNK1 and JNK2 (c-Jun N-terminal kinases) working in concert. We have demonstrated that FDH induces phosphorylation of JNK1 and JNK2, while treatment of FDH-expressing cells with JNK inhibitor SP600125, as well as knockdown of JNK1 or JNK2 by siRNA, prevents phosphorylation of p53 at Ser6 and protects cells from apoptosis. Interestingly, the knockdown of JNK1 abolished phosphorylation of JNK2 in response to FDH, while knockdown of JNK2 did not prevent JNK1 phosphorylation. Pull-down assay with the p53-specific antibody has shown that JNK2, but not JNK1, is physically associated with p53. Our studies revealed a novel mechanism in which phosphorylation of JNK2 is mediated by JNK1 before phosphorylation of p53, and then p53 is directly phosphorylated by JNK2 at Ser6.