Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer
| Autor: | Jiayi, Wang, Lifang, Ma, Wenhao, Weng, Yongxia, Qiao, Yue, Zhang, Jiangtu, He, Hongmei, Wang, Weifan, Xiao, Lanlan, Li, Qinghua, Chu, Qiuhui, Pan, Yongchun, Yu, Fenyong, Sun |
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| Rok vydání: | 2013 |
| Předmět: |
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Physiological Carcinoma Hepatocellular Carcinogenesis Cell Survival Liver Neoplasms Mice Nude YAP-Signaling Proteins In Vitro Techniques Phosphoproteins beta-Transducin Repeat-Containing Proteins p38 Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinase 14 Mice Cell Transformation Neoplastic Cell Line Tumor Animals Heterografts Homeostasis Humans Phosphorylation Cyclic AMP Response Element-Binding Protein Cells Cultured Adaptor Proteins Signal Transducing Transcription Factors |
| Zdroj: | Hepatology (Baltimore, Md.). 58(3) |
| ISSN: | 1527-3350 |
| Popis: | 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.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. |
| Databáze: | OpenAIRE |
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