AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation
AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation
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AXIN 是 p53 激活中早幼粒细胞白血病蛋白的重要共激活剂
DOI：
10.1038/onc.2010.499
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发表时间：
2011-03-01
期刊：
影响因子：
8
通讯作者：
Lin, S-C
中科院分区：
文献类型：
--
作者：
Li, Q.;He, Y.;Lin, S-C
PML蛋白最为人所知的是其作为急性早幼粒细胞白血病的肿瘤抑制剂的作用。PML和关键的Wnt信号调节因子AXIN均调节p53依赖性细胞凋亡以响应DNA损伤。然而，这两种主要的肿瘤抑制因子如何相互协调尚不清楚，并且协调PML诱导的细胞凋亡的分子组分仍然是谜。在这里，我们表明，轴蛋白与PML在体内相互作用，并进一步轴蛋白，PML和p53形成三元复合物。暴露于遗传毒性信号（包括UV和阿霉素）可诱导轴蛋白进入细胞核，并与核体中的PML共定位。结构域作图实验表明，AXIN的C-末端区域（aa 597-832）负责其与PML的相互作用。AXIN不能激活PML−/−细胞中的p53，相反，PML不能激活AXIN缺失的SNU 475细胞中的p53。一致地，用各自的siRNA敲低揭示了AXIN和PML在用基因毒素处理后相互依赖以提高p53-Ser-46磷酸化并诱导凋亡。此外，我们发现PML的显性失活突变体阻断了AXIN诱导的p53激活，并且AXIN促进PML类小泛素化，这是PML功能所必需的修饰。因此，我们的发现为理解PML激活p53并发挥其肿瘤抑制作用的机制提供了新的途径。
The PML protein is best known for its role as a tumor suppressor for acute promyelocytic leukemia. Both PML and the key Wnt signaling regulator AXIN regulate p53-dependent apoptosis in response to DNA damage. However, how the two major tumor suppressors coordinate with each other is unknown, and the molecular components orchestrating the PML-induced apoptosis remain enigmatic. Here we show that AXIN interacts with PML in vivo, and further that AXIN, PML and p53 form a ternary complex. Exposure to genotoxic signals including UV and doxorubicin induces AXIN to enter into the nucleus where it colocalizes with PML in the nuclear bodies. Domain-mapping experiments revealed that the C-terminal region (aa 597–832) of AXIN is responsible for its interaction with PML. AXIN fails to activate p53 in PML−/− cells, and conversely, PML is unable to activate p53 in AXIN-null SNU475 cells. Consistently, knockdown with respective siRNAs revealed that AXIN and PML depend on each other to elevate p53-Ser-46 phosphorylation and to induce apoptosis after treatment with genotoxins. Moreover, we found that dominant-negative mutants of PML blocked AXIN-induced p53 activation, and that AXIN promotes PML sumoylation, a modification necessary for PML functions. Our finding has thus provided a new avenue for understanding the mechanism by which PML activates p53 and exerts its role as a tumor suppressor.