Mutual Interaction Between YAP and CREB Promotes Tumorigenesis in Liver Cancer
Mutual Interaction Between YAP and CREB Promotes Tumorigenesis in Liver Cancer
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DOI：
10.1002/hep.26420
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发表时间：
2013-09-01
期刊：
影响因子：
13.5
通讯作者：
Sun, Fenyong
中科院分区：
文献类型：
--
作者：
Wang, Jiayi;Ma, Lifang;Sun, Fenyong
是相关蛋白（雅普），海马信号通路的下游效应器以及环磷酸腺苷反应元件结合蛋白（CREB），已被链接到肝癌的发生。然而，很少有人知道雅普和CREB是否以及如何相互作用。在这项研究中，我们发现YAP-CREB相互作用对于肝癌细胞存活和维持转化表型至关重要，无论是在体外还是在体内。此外，CREB和雅普蛋白在人肝癌样品的子集中高度表达并且密切相关。CREB通过与雅普启动子的新区域--608/-439结合促进雅普转录输出。相比之下，雅普通过与促分裂原活化蛋白激酶14（MAPK 14/p38）和β-转导素重复序列包含的E3泛素蛋白连接酶（BTRC）相互作用促进CREB的蛋白稳定。功能获得和功能丧失的研究表明，CREB的磷酸化的MAPK 14/p38在ser 133最终导致其降解。BTRC可通过MAPK 14/p38在Thr 180/Tyr 182处的磷酸化来增强这种作用。然而，雅普通过抑制BTRC表达负性控制MAPK 14/p38的磷酸化。结论：肝癌中雅普和CREB之间存在一个新的正性自身调节反馈环，提示雅普和CREB在癌细胞中形成了整合蛋白激酶A、Hippo/雅普和MAPK 14/p38通路的联系，因此可能有助于肝癌有效诊断和治疗策略的发展。（肝病学2013;53：1011-1020）
Yes-associated protein (YAP), the downstream effecter of the Hippo-signaling pathway as well as cyclic adenosine monophosphate response element-binding protein (CREB), has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interact with each other. In this study, we found that YAP-CREB interaction is critical for liver cancer cell survival and maintenance of transformative phenotypes, both in vitro and in vivo. Moreover, both CREB and YAP proteins are highly expressed in a subset of human liver cancer samples and are closely correlated. Mechanistically, CREB promotes YAP transcriptional output through binding to -608/-439, a novel region from the YAP promoter. By contrast, YAP promotes protein stabilization of CREB through interaction with mitogen-activated protein kinase 14 (MAPK14/p38) and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Gain-of-function and loss-of-function studies demonstrated that phosphorylation of CREB by MAPK14/p38 at ser133 ultimately leads to its degradation. Such effects can be enhanced by BTRC through phosphorylation of MAPK14/p38 at Thr180/Tyr182. However, YAP negatively controls phosphorylation of MAPK14/p38 through inhibition of BTRC expression. Conclusion: There is a novel positive autoregulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting that YAP and CREB form a nexus to integrate the protein kinase A, Hippo/YAP, and MAPK14/p38 pathways in cancer cells and thus may be helpful in the development of effective diagnosis and treatment strategies against liver cancer. (Hepatology 2013;53:1011-1020)