MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1.
MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1.
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DOI：
10.1016/j.cell.2015.01.028
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发表时间：
2015-02-12
期刊：
影响因子：
64.5
通讯作者：
Dai C
中科院分区：
文献类型：
--
作者：
Tang Z;Dai S;He Y;Doty RA;Shultz LD;Sampson SB;Dai C
通过RAS/MAP激酶途径的信号传导是生物学的核心。ERK一直被认为是MEK的唯一底物。在这里，我们报告说，HSF 1，主调节蛋白毒性应激反应，是一个新的MEK底物。除了介导细胞-环境相互作用外，MEK-HSF 1调节还影响恶性肿瘤。在肿瘤细胞中，MEK阻断使HSF 1失活，从而引起蛋白质组学混乱，表现为蛋白质不稳定、聚集和引人注目的淀粉样蛋白生成。与它们的非转化对应物不同，肿瘤细胞特别容易受到蛋白质组学干扰和淀粉样蛋白诱导。淀粉样蛋白生成是肿瘤抑制性的，减少体内黑色素瘤生长并有助于蛋白毒性应激物的有效抗肿瘤作用。我们的发现揭示了致癌RAS-MEK信号在保护蛋白质稳态和抑制淀粉样蛋白生成中的关键生物学功能。因此，蛋白质组不稳定性是恶性状态的内在特征，破坏脆弱的肿瘤蛋白质稳态以促进淀粉样蛋白生成可能是一种可行的治疗策略。
Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Herein we report that HSF1, the master regulator of the proteotoxic stress response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor-suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state and, disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.