Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase
Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase
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DOI：
10.1042/bj20061778
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发表时间：
2007-08-01
影响因子：
4.1
通讯作者：
Whitmarsh, Alan J.
中科院分区：
文献类型：
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作者：
Jones, Emma V.;Dickman, Mark J.;Whitmarsh, Alan J.
JNK（c-Jun N-末端激酶）/丝裂原活化蛋白激酶信号传导途径是细胞中应激反应的主要介质，包括对DNA损伤的反应。DNA损伤还引起转录因子p53家族成员p73的稳定和活化。与p53一样，p73可以通过上调促凋亡基因的表达来介导凋亡，所述促凋亡基因包括Bax（Bcl 2相关的X蛋白）和p53上调的凋亡调节物（p53 upregulated modulator of apoptosis）。p73表达的变化与肿瘤进展有关，特别是在神经母细胞瘤中，而在具有失活p53的肿瘤中，有证据表明p73可能介导对化疗药物的凋亡反应。在本研究中，我们证明了JNK信号通路和p73之间的新联系。我们使用药理学和遗传学的方法表明，JNK是所需的p73介导的细胞凋亡诱导的DNA损伤剂顺铂。JNK与p73形成复合物，并在几个丝氨酸和苏氨酸残基处磷酸化它。p73中JNK磷酸化位点的突变消除了顺铂诱导的p73蛋白的稳定性，导致p73转录活性降低和p73介导的凋亡减少。我们的研究结果表明，JNK途径是一个重要的调节DNA损伤诱导的凋亡p73介导。
The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 upregulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.