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 check details 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). selleck inhibitor 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 上海皓元医药股份有限公司 may be helpful in the development of effective diagnosis and treatment strategies against liver cancer. (Hepatology 2013;53:1011–1020) Liver cancer is the fifth-most common cancer worldwide and the third-leading cause of cancer death.[1] The treatment options for these hepatic malignancies are extremely limited, mainly because the mechanisms of pathogenesis of these cancers are

not completely known. Recently, the dysfunctional Hippo/Yes-associated protein (YAP)-signaling pathway has been linked to hepatocarcinogenesis.[2] Transgenic mice with liver-targeted YAP overexpression demonstrated a dramatic increase in liver size and eventually developed tumors.[3] In addition, clinical studies revealed that YAP was overexpressed in 62% of hepatocellular carcinoma (HCC) patients and was an independent predictor associated with poor disease-free survival and overall survival in HCC.[4] In view of the vital roles that YAP plays in the development of liver cancer, it was extremely important to understand how YAP is up-regulated in tumor. Numerous studies have shown that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) may be involved in liver cancer development. CREB is a ubiquitous transcription factor that activates the transcriptional activity of various promoters through its binding site.