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The Hippo pathway in normal development and cancer
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2018-01-03 , DOI: 10.1016/j.pharmthera.2017.12.011
Marcello Maugeri-Saccà , Ruggero De Maria

The Hippo pathway is a central regulator of organ size and tissue homeostasis. Hippo kinases and adaptor proteins mediate the phosphorylation and inactivation of YAP and TAZ, two closely related transcription co-activators. The Hippo pathway responds to a variety of extracellular and intracellular signals, spanning from cell-cell contact and mechanical cues to ligands of G-protein-coupled receptors and metabolic avenues. In some instances, YAP/TAZ activation is tuned by forces that bypass the Hippo kinase module, adding further complexity to the biology of the pathway. Over the past two decades, the Hippo pathway has increasingly been connected with developmental processes and tissue repair, being intimately tied to the function of tissue-specific progenitor cells. Pervasive activation of YAP/TAZ has been recognized in a multitude of human tumors and connected with the acquisition of malignant traits, including resistance to anticancer therapies, distant dissemination and maintenance of cancer stem cells. On this ground, Hippo-related biomarkers are increasingly investigated in translational studies striving to identify prognostic and predictive factors. In addition, the dependency of many tumors on YAP/TAZ may be exploited for therapeutic purposes. Albeit no direct inhibitors are currently available, drug repositioning approaches provided hints that YAP/TAZ inhibition can be achieved with old drugs, such as cholesterol-lowering agents or compounds blocking bone resorption.



中文翻译:

正常发育和癌症中的河马途径

河马途径是器官大小和组织动态平衡的中央调节器。河马激酶和衔接蛋白介导两个密切相关的转录共激活因子YAP和TAZ的磷酸化和失活。Hippo途径对多种细胞外和细胞内信号作出反应,范围从细胞与细胞的接触和机械提示到G蛋白偶联受体和代谢途径的配体。在某些情况下,通过绕过Hippo激酶模块的作用力可以调节YAP / TAZ的激活,从而进一步增加了途径生物学的复杂性。在过去的二十年中,Hippo途径与发育过程和组织修复的联系日益紧密,与组织特异性祖细胞的功能密切相关。YAP / TAZ的普遍活化已在许多人类肿瘤中得到公认,并与恶性特征的获得有关,包括对抗癌疗法的抗性,远距离散布和癌干细胞的维持。因此,在翻译研究中越来越多地研究与河马相关的生物标志物,以寻找预后和预测因素。另外,可以将许多肿瘤对YAP / TAZ的依赖性用于治疗目的。尽管目前尚无直接抑制剂,但药物重新定位方法提示使用旧药物(例如降低胆固醇的药物或阻止骨吸收的化合物)可以实现YAP / TAZ抑制。癌症干细胞的远距离传播和维持。因此,在翻译研究中越来越多地研究与河马相关的生物标志物,以寻找预后和预测因素。另外,可以将许多肿瘤对YAP / TAZ的依赖性用于治疗目的。尽管目前尚无直接抑制剂,但药物重新定位方法提示使用旧药物(例如降低胆固醇的药物或阻止骨吸收的化合物)可以实现YAP / TAZ抑制。癌症干细胞的远距离传播和维持。因此,在翻译研究中越来越多地研究与河马相关的生物标志物,以寻找预后和预测因素。另外,可以将许多肿瘤对YAP / TAZ的依赖性用于治疗目的。尽管目前尚无直接抑制剂,但药物重新定位方法提示使用旧药物(例如降低胆固醇的药物或阻止骨吸收的化合物)可以实现YAP / TAZ抑制。

更新日期:2018-01-03
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