The Ets Transcription Factor GABP Is a Component of the Hippo Pathway Essential for Growth and Antioxidant Defense

The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen-induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP. [Display omitted] •The heterodimeric Ets transcription factor GABP is required for YAP expression•YAP is an important downstream effector of GABP for cell survival and proliferation•The Hippo pathway regulates the activity of GABP by phosphorylation•YAP is essential for cellular and tissue defenses against oxidative stress Yap is an important downstream effector of the Hippo pathway. However, how Yap gene expression is regulated remains elusive. In this study, Zhou, Chen and colleagues demonstrate that the Ets family member GABP is critical for Yap gene expression and that GABP activity is regulated by the Hippo pathway. They find that GABP-mediated YAP expression protects mice from acetaminophen-induced liver injury and that expression of both GABP and YAP is enhanced in human liver cancers. Therefore, GABP is a potential therapeutic target for liver diseases.