Molecular Chemoprevention Group, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome, Italy.
Cell Death Differ. 2013 Nov;20(11):1498-509. doi: 10.1038/cdd.2013.101. Epub 2013 Aug 9.
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.
Werner 综合征（WS）是由 WRN 蛋白功能障碍引起的，与早衰和早逝有关。在这里，我们报告说，WRN 功能的丧失会引发 Yes 相关蛋白（YAP 蛋白）的积累，YAP 蛋白是 Hippo 肿瘤抑制途径的主要效应物，这在实验中和 WS 衍生的成纤维细胞中都得到了证实。YAP 的上调与细胞增殖减缓和衰老加速相关，这部分是由 YAP 与 PML 蛋白形成复合物介导的，其活性促进 p53 的激活。ATM 激酶对于 WRN 耗尽细胞中 YAP 和 PML 的积累是必需的。值得注意的是，YAP 或 PML 的耗竭部分削弱了 WRN 缺失后衰老的诱导。总之，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。衰老相关分泌表型（SASP）具有促肿瘤特性，其特性可被 YAP、PML 和 p53 的耗竭所增强。
