Evidence map›Paper›PMID 25249570›Full record

ArticleCirculation research2015

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

Zhiqiang Lin, Pingzhu Zhou, Alexander von Gise, Fei Gu, Qing Ma, Jinghai Chen, Haidong Guo, Pim R R van Gorp, Da-Zhi Wang, William T Pu

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Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 209 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
209citing papers in PubMed, 1 pooled it
9.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

209 citing papers in PubMed, 1 synthesis or guideline pooled it, 297 citations in OpenAlex.

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149 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 4 countries.

Zhiqiang LinFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Pingzhu ZhouFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Alexander von GiseFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Fei GuFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Qing MaFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Jinghai ChenFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Haidong GuoFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Pim R R van GorpFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
Da-Zhi WangFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.).
William T PuFrom the Department of Cardiology, Boston Children's Hospital, MA (Z.L., P.Z., A.v.G., F.G., Q.M., J.C., H.G., P.R.R.v.G., D.-Z.W., W.T.P.); Department of Pediatric Cardiology and Intensive Care, MHH-Hannover Medical School, Hannover, Germany (A.v.G.); Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China (H.G.); Department of Cardiology, Leiden University Medical Center, The Netherlands (P.R.R.v.G.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W., W.T.P.). wpu@enders.tch.harvard.edu.
Shanghai University of Traditional Chinese Medicine · CNHarvard University · USMedizinische Hochschule Hannover · DE

Funding

Mapping Transcriptional Networks in Cardiac DevelopmentU01HL098166 · NHLBI · HARVARD MEDICAL SCHOOL · PI SEIDMAN, JONATHAN G · 2009 to 2014
$9.5M
Microenvironmental control of progenitors in organ dysfunction and repairU01HL100401 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI OLSON, ERIC N, SCHNEIDER, JAY W · 2009 to 2015
$8.3M
YAP1 Regulation of cardiomyocyte proliferation, function, and regenerationR01HL116461 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI PU, WILLIAM TSWENCHING · 2013 to 2017
$2.6M
Regulation of Heart Function by a Gata4-Fog2 transcriptional complexR01HL095712 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI PU, WILLIAM TSWENCHING · 2010 to 2013
$1.7M
NHLBI NIH HHS HL095712NHLBI NIH HHS HL100401NHLBI NIH HHS R01 HL095712NHLBI NIH HHS R01 HL116461NHLBI NIH HHS U01 HL098166NHLBI NIH HHS U01HL098166NHLBI NIH HHS U01 HL100401
6 · The paper itself

Abstract

rationaleYes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain 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.

objectiveTo identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. METHODS AND

resultsWe 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 Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression.

conclusionsPik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival.

Indexed as

AnimalsAnimals, NewbornApoptosis Regulatory ProteinsBase SequenceCell ProliferationCells, CulturedCell SurvivalClass Ib Phosphatidylinositol 3-KinaseHippo Signaling PathwayMiceMolecular Sequence DataMyocytes, CardiacProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktRatsSignal TransductionApoptosis Regulatory ProteinsClass Ib Phosphatidylinositol 3-KinaseProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktYap1 protein, ratYAP-Signaling ProteinsAAVAktheart failureHippoPI3 kinasePik3cbregenerationYap

Identifiers

PMID25249570
PMCPMC4282610
OpenAlexW2122118690

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Read underepoch 390

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.