Circulation Research RES <i>Pi3kcb</i> Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival <i>Pik3cb</i> Links Hippo-YAP and PI3K-AKT Pathways CIRCRES/2014/304457 CIRCRES/2014/304457 10.1161/CIRCRESAHA.115.304457 115 12/05/14 12 Bridges-Lyman Gemma 410-3275005 410-3279322 Marian, Ali University of Texas Health Science Center Dr. William T Pu wpu@enders.tch.harvard.edu Dr. Harvard Medical School 300 Longwood Ave Boston Massachusetts 02115 UNITED STATES 617-919-2091 15491 Zhiqiang Lin Harvard Medical School zlin@enders.tch.harvard.edu 93218 Pingzhu Zhou Harvard Medical School pzhou@enders.tch.harvard.edu 156966 Alexander von Gise Boston Children's Hospital avgise@pulab.org 214275 Fei Gu Boston Children's Hospital fgu@enders.tch.harvard.edu 195970 Qing Ma Harvard Medical School Qing.Ma@childrens.harvard.edu 156967 Jinghai Chen Harvard Medical School jichen@enders.tch.harvard.edu 93211 Haidong Guo Boston Children's Hospital hdguo8@hotmail.com 217103 Pim RR van Gorp Leiden University Medical Center pimvan_gorp12@hotmail.com 156973 Da-Zhi Wang Harvard Medical School dwang@enders.tch.harvard.edu 7237 William T Pu Harvard Medical School wpu@enders.tch.harvard.edu 15491 05/26/2014 05/26/2014 09/18/2014 09/23/2014 09/23/2014 Regular Article Akt cardiomyocyte proliferation hippo Pik3cb YAP <p><i><b><u>Rationale:</u></b></i> YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. </p><p><i><b><u>Objective:</u></b></i> To identify direct YAP targets that mediate its mitogenic and anti-apoptotic effects in the heart. </p><p><i><b><u>Methods and Results:</u></b></i> We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified <i>Pik3cb</i>, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEAD occupied a conserved enhancer within the first intron of <i>Pik3cb</i>, and this enhancer drove YAP-dependent reporter gene expression. <i>Yap</i> gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like <i>Yap</i>, <i>Pik3cb</i> gain-of-function stimulated cardiomyocyte proliferation, and <i>Pik3cb</i> knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in <i>Yap</i> loss-of-function was significantly rescued by AAV-mediated <i>Pik3cb</i> expression. </p><p><i><b><u>Conclusions:</u></b></i> <i>Pik3cb</i> is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. </p> 0 0 1 7 8 yes CircRes_CIRCRES-2014-304457.xml

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CircRes_CIRCRES-2014-304457_supp1.xlsx CircRes_CIRCRES-2014-304457_supp2.xlsx CircRes_CIRCRES-2014-304457_file1.docx CircRes_CIRCRES-2014-304457_supp3.pdf CircRes_CIRCRES-2014-304457_supp4.pdf CircRes_CIRCRES-2014-304457_merge.pdf CircRes_CIRCRES-2014-304457_Pu_15491_disclosure.pdf CircRes_CIRCRES-2014-304457_Pu_15491_copyright.pdf CircRes_CIRCRES-2014-304457_Ma_156967_disclosure.pdf CircRes_CIRCRES-2014-304457_Ma_156967_copyright.pdf CircRes_CIRCRES-2014-304457_Guo_217103_disclosure.pdf CircRes_CIRCRES-2014-304457_Guo_217103_copyright.pdf CircRes_CIRCRES-2014-304457_Wang_7237_disclosure.pdf CircRes_CIRCRES-2014-304457_Wang_7237_copyright.pdf CircRes_CIRCRES-2014-304457_Lin_93218_disclosure.pdf CircRes_CIRCRES-2014-304457_Lin_93218_copyright.pdf CircRes_CIRCRES-2014-304457_Zhou_156966_disclosure.pdf CircRes_CIRCRES-2014-304457_Zhou_156966_copyright.pdf CircRes_CIRCRES-2014-304457_Gu_195970_disclosure.pdf CircRes_CIRCRES-2014-304457_Gu_195970_copyright.pdf CircRes_CIRCRES-2014-304457_Chen_93211_disclosure.pdf CircRes_CIRCRES-2014-304457_Chen_93211_copyright.pdf CircRes_CIRCRES-2014-304457_van_Gorp_156973_disclosure.pdf CircRes_CIRCRES-2014-304457_van_Gorp_156973_copyright.pdf CircRes_CIRCRES-2014-304457_von_Gise_214275_disclosure.pdf CircRes_CIRCRES-2014-304457_von_Gise_214275_copyright.pdf PAP: 09/23/14 Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: No Wellcome Trust: No Subject Codes: [138] Cell signaling/signal transduction [143] Gene regulation [148] Heart failure - basic studies gbridgeslyman