Identification of Kinases Responsible for p53-Dependent Autophagy.
Identification of Kinases Responsible for p53-Dependent Autophagy.
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负责 p53 依赖性自噬的激酶的鉴定。
DOI：
10.1016/j.isci.2019.04.023
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发表时间：
2019
期刊：
影响因子：
5.8
通讯作者：
MacKeigan,JeffreyP
中科院分区：
文献类型：
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作者：
Celano,StephanieL;Yco,LisetteP;Kortus,MatthewG;Solitro,AbigailR;Gunaydin,Hakan;Scott,Mark;Spooner,Edward;O'Hagan,RonanC;Fuller,Peter;Martin,KatieR;Shumway,StuartD;MacKeigan,JeffreyP
在癌症中，自噬在营养应激期间被上调，以促进细胞存活和肿瘤生长，并可以赋予对药物治疗的抵抗力。几个主要信号网络控制自噬诱导，包括 p53 肿瘤抑制通路。为了响应 DNA 损伤和其他细胞应激，p53 被稳定并激活，而 HDM2 结合并泛素化 p53 以进行蛋白酶体降解。因此，阻断 HDM2-p53 相互作用是一种有前景的癌症治疗策略。然而，自噬诱导带来的潜在生存优势可能会限制治疗效果。在这项研究中，我们利用 HDM2 抑制剂来鉴定 p53 依赖性自噬所需的激酶。有趣的是，我们发现p53依赖性自噬需要多种激酶，包括强直性肌营养不良蛋白激酶样α（MRCKα）。 MRCKα 是一种 CDC42 效应子，据报道可激活肌动蛋白-肌球蛋白细胞骨架重组。总的来说，这项研究提供了将 MRCKα 与自噬联系起来的证据，并揭示了激酶在 p53 依赖性自噬中的作用的更多见解。
In cancer, autophagy is upregulated to promote cell survival and tumor growth during times of nutrient stress and can confer resistance to drug treatments. Several major signaling networks control autophagy induction, including the p53 tumor suppressor pathway. In response to DNA damage and other cellular stresses, p53 is stabilized and activated, while HDM2 binds to and ubiquitinates p53 for proteasome degradation. Thus blocking the HDM2-p53 interaction is a promising therapeutic strategy in cancer; however, the potential survival advantage conferred by autophagy induction may limit therapeutic efficacy. In this study, we leveraged an HDM2 inhibitor to identify kinases required for p53-dependent autophagy. Interestingly, we discovered that p53-dependent autophagy requires several kinases, including the myotonic dystrophy protein kinase-like alpha (MRCKα). MRCKα is a CDC42 effector reported to activate actin-myosin cytoskeletal reorganization. Overall, this study provides evidence linking MRCKα to autophagy and reveals additional insights into the role of kinases in p53-dependent autophagy.