Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.
Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.
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DOI：
10.1161/circresaha.115.304457
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发表时间：
2015-01-02
影响因子：
20.1
通讯作者：
Pu WT
中科院分区：
文献类型：
--
作者：
Lin Z;Zhou P;von Gise A;Gu F;Ma Q;Chen J;Guo H;van Gorp PR;Wang DZ;Pu WT
雅普是Hippo信号传导的核效应子，通过与TEAD序列特异性DNA结合蛋白相互作用来调节包括心脏在内的多个器官中的细胞生长和存活。最近的研究表明，雅普刺激心肌细胞增殖和存活。然而，雅普发挥其作用的直接转录靶点定义不清。鉴定介导其心脏促有丝分裂和抗凋亡作用的直接雅普靶点。我们通过结合雅普功能获得和丧失中的差异基因表达分析与使用染色质免疫沉淀和高通量测序的雅普结合位点的全基因组鉴定来鉴定直接雅普靶点。该筛选鉴定了编码磷酸肌醇-3-激酶（PI 3 K）的催化亚基p110β的Pik 3cb作为促进心肌细胞增殖和存活的候选雅普效应物。雅普和TEAD占据Pik 3cb第一内含子内的保守增强子，并且该增强子驱动YAP依赖的报告基因表达。雅普功能获得和丧失研究表明，雅普是激活PI 3 K-Akt通路所必需的和充分的。像雅普一样，Pik 3cb功能获得性刺激心肌细胞增殖，Pik 3cb敲低抑制雅普促有丝分裂活性。反过来，雅普功能丧失的受损心脏功能被AAV介导的Pik 3cb表达显著挽救。Pik 3cb是雅普的重要直接靶点，雅普通过Pik 3cb激活PI 3 K-AKT通路，调节心肌细胞增殖和存活。
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. To identify direct YAP targets that mediate its’ mitogenic and anti-apoptotic effects in the heart. 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 Pik3cb, 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 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 PI3K-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 AAV-mediated Pik3cb expression. : Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKTpathway and regulates cardiomyocyte proliferation and survival.