Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation
Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation
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DOI：
10.1038/sj.emboj.7600475
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发表时间：
2004-11-24
期刊：
影响因子：
11.4
通讯作者：
Lin, SC
中科院分区：
文献类型：
--
作者：
Rui, YN;Xu, Z;Lin, SC
Axin和p53是肿瘤抑制因子，控制细胞生长、凋亡和发育。我们表明，Axin与同源结构域相互作用蛋白激酶2（HIPK2），这是连接到紫外线诱导的p53依赖性细胞凋亡的相互作用，并磷酸化丝氨酸46，p53。除了通过HIPK2与p53结合外，Axin还含有一个单独的结构域，可以在生理浓度下直接与p53相互作用。Axin在293细胞中刺激p53依赖性报告基因转录，但在p53信号传导缺陷的293T、H1299或SaOS-2细胞中不刺激。Axin（而不是AxinDeltaHIPK2）激活HIPK2介导的p53第46位丝氨酸磷酸化，促进p53依赖性转录活性和细胞凋亡。通过siRNA特异性敲低Axin可减少UV诱导的Ser-46磷酸化和细胞凋亡。激酶死亡的HIPK2降低了Axin诱导的p53依赖性转录活性，表明Axin通过HIPK2激酶活性刺激p53功能。有趣的是，缺乏Axin结合区的HIPK2 Δ Axin在p53激活中作为显性阳性形式，表明HIPK2的Axin结合区是推定的自身抑制结构域。这些结果表明，Axin通过整合多种因子促进p53功能而发挥肿瘤抑制剂的作用。
Axin and p53 are tumor suppressors, controlling cell growth, apoptosis, and development. We show that Axin interacts with homeodomain-interacting protein kinase-2 (HIPK2), which is linked to UV-induced p53-dependent apoptosis by interacting with, and phosphorylating Ser 46 of, p53. In addition to association with p53 via HIPK2, Axin contains a separate domain that directly interacts with p53 at their physiological concentrations. Axin stimulates p53-dependent reporter transcription in 293 cells, but not in 293T, H1299, or SaOS-2 cells that are defective in p53 signaling. Axin, but not AxinDeltaHIPK2, activates HIPK2-mediated p53 phosphorylation at Ser 46, facilitating p53-dependent transcriptional activity and apoptosis. Specific knockdown of Axin by siRNA reduced UV-induced Ser-46 phosphorylation and apoptosis. Kinase-dead HIPK2 reduced Axin-induced p53-dependent transcriptional activity, indicating that Axin stimulates p53 function through HIPK2 kinase activity. Interestingly, HIPK2DeltaAxin that lacks its Axin-binding region acts as a dominant-positive form in p53 activation, suggesting that the Axin-binding region of HIPK2 is a putative auto-inhibitory domain. These results show that Axin acts as a tumor suppressor by facilitating p53 function through integration of multiple factors.