ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence
ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence
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DOI：
10.1038/cdd.2013.101
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发表时间：
2013-11-01
影响因子：
12.4
通讯作者：
Blandino, G.
中科院分区：
文献类型：
--
作者：
Fausti, F.;Di Agostino, S.;Blandino, G.
沃纳综合征 (WS) 是由 WRN 蛋白功能障碍引起的，与过早衰老和过早死亡有关。在这里，我们报告说，WRN 功能的丧失会引起 Yes 相关蛋白（YAP 蛋白）的积累，YAP 蛋白是 Hippo 肿瘤抑制通路的主要效应物，无论是在实验上还是在 WS 衍生的成纤维细胞中都是如此。 YAP 上调与细胞增殖减慢和衰老加速相关，这部分是由 YAP 和 PML 蛋白之间复合物的形成介导的，该复合物的活性促进 p53 激活。 ATM 激酶对于 WRN 耗尽的细胞中 YAP 和 PML 的积累是必需的。值得注意的是，YAP 或 PML 的消耗部分损害了 WRN 丢失后的衰老诱导。总而言之，我们的研究结果表明，WRN 活性的丧失会触发 ATM-YAP-PML-p53 轴的激活，从而加速细胞衰老。后者具有 SASP（衰老相关分泌表型）的特征，其促肿瘤特性因 YAP、PML 和 p53 耗竭而增强。
Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.