Differential regulation of Apak by various DNA damage signals
Differential regulation of Apak by various DNA damage signals
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DOI：
10.1007/s11010-009-0218-y
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发表时间：
2009
影响因子：
4.3
通讯作者：
Shan-shan Wang;Chunyan Tian;Ting Xiao;G. Xing;F. He;Lingqiang Zhang;Hong Chen
中科院分区：
文献类型：
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作者：
Shan-shan Wang;Chunyan Tian;Ting Xiao;G. Xing;F. He;Lingqiang Zhang;Hong Chen
肿瘤抑制因子p53位于蛋白质信号网络的中心，该网络响应于多种类型的应激，并且p53激活导致细胞周期停滞或凋亡。我们最近发现ATM和p53相关的KZNF蛋白（Apak）是p53介导的凋亡的负调节因子。在用甲磺酸甲酯（MMS）处理细胞后，Apak被ATM激酶磷酸化并与p53解离，导致p53活化并诱导凋亡。然而，Apak响应于其他类型的DNA损伤信号的调节机制仍不清楚。在这里，我们发现，我们检查的七种类型的DNA损伤信号（诱导依托泊苷，阿霉素，喜树碱和顺铂治疗）导致显着的Apak磷酸化和Apak从p53解离，释放抑制p53转录活性。相反，Apak在5-氟尿嘧啶或α-硫辛酸处理后在Ser 68处不磷酸化，并持续抑制p53活性。这些发现提供了Apak-p53相互作用受各种DNA损伤信号差异调节的证据。
The tumor suppressor p53 lies at the center of a protein-signaling network that responds to many types of stress, and p53 activation leads to cell cycle arrest or apoptosis. We recently identifiedATM andp53-associatedKZNF protein (Apak) as a negative regulator of p53-mediated apoptosis. After treatment of cells with methyl methanesulfonate (MMS), Apak is phosphorylated by ATM kinase and dissociates from p53, resulting in p53 activation and induction of apoptosis. However, the mechanism by which Apak is regulated in response to other types of DNA damage signals remains unclear. Here, we show that four of seven types of DNA damage signals we examined (induction by etoposide, doxorubicin, camptothecin and cisplatin treatment) resulted in significant Apak phosphorylation and dissociation of Apak from p53, releasing the inhibition of p53 transcriptional activity. In contrast, Apak was not phosphorylated at Ser68 after 5-fluorouracil or α-lipoic acid treatment and persistently inhibited p53 activity. These findings provide evidence that the Apak-p53 interaction is regulated differentially by various DNA damage signals.