title: The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense.
abstract: 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.
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiang'an District, Xiamen, Fujian 361102, China.
authors.forename: Hongtan
authors.initials: H
authors.lastname: Wu
authors.forename: Yubo
authors.initials: Y
authors.lastname: Xiao
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhang
authors.forename: Suyuan
authors.initials: S
authors.lastname: Ji
authors.forename: Luyao
authors.initials: L
authors.lastname: Wei
authors.forename: Fuqin
authors.initials: F
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Geng
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Sun
authors.forename: Funiu
authors.initials: F
authors.lastname: Qin
authors.forename: Changnan
authors.initials: C
authors.lastname: Jin
authors.forename: Jianjun
authors.initials: J
authors.lastname: Lin
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Yin
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Lianzhong
authors.initials: L
authors.lastname: Luo
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Siyang
authors.initials: S
authors.lastname: Song
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Fernando
authors.initials: F
authors.lastname: Camargo
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051268:GA-Binding Protein Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D000082:Acetaminophen; D000975:Antioxidants; D018797:Cell Cycle Proteins; D051268:GA-Binding Protein Transcription Factor; D017228:Hepatocyte Growth Factor; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C082332:macrophage stimulating protein; C092745:LATS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases