Axin determines cell fate by controlling the p53 activation threshold after DNA damage
Axin determines cell fate by controlling the p53 activation threshold after DNA damage
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Axin 通过控制 DNA 损伤后 p53 激活阈值来决定细胞命运
DOI：
10.1038/ncb1927
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发表时间：
2009-09-01
影响因子：
21.3
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Li, Qinxi;Lin, Shuyong;Lin, Sheng-Cai
基于p53活性，在遗传毒性应激后，细胞可以经历细胞周期停滞或凋亡（1-6）。在这里，我们表明，细胞命运的承诺取决于Axin与Pirh 2，Tip 60，HIPK 2和p53形成不同的复合物。在用亚致死剂量的紫外线（UV）辐射或多柔比星（Dox）处理的细胞中，Pirh 2通过与HIPK 2竞争结合Axin来消除由HIPK 2催化的Axin诱导的p53在Ser 46处的磷酸化。然而，在致死处理时，Tip 60与Axin相互作用并消除Pirh 2-Axin结合，形成Axin-Tip 60-HIPK 2-p53复合物，其允许最大p53激活以触发凋亡。我们还提供了ATM/ATR途径介导Axin-Tip 60复合物组装的证据。Axin突变促进Axin（Fu）/+（Axin-Fused）小鼠的致癌作用，与Axin（Fu）在p53激活中的显性负作用一致。因此，Axin是p53依赖性肿瘤抑制中的关键决定因素，其中Pirh 2和Tip 60在触发细胞周期停滞或凋亡中具有不同的作用，这取决于遗传毒性应激的严重程度。
Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity(1-6). Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2-Axin binding, forming an Axin-Tip60-HIPK2-p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the Axin-Tip60 complex assembly. An axin mutation promotes carcinogenesis in Axin(Fu)/+ (Axin-Fused) mice, consistent with a dominant-negative role for Axin(Fu) in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress.