GATA4 regulates ANF expression synergistically with Sp1 in a cardiac hypertrophy model.
GATA4 regulates ANF expression synergistically with Sp1 in a cardiac hypertrophy model.
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GATA4 在心脏肥大模型中与 Sp1 协同调节 ANF 表达
DOI：
10.1111/j.1582-4934.2010.01182.x
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发表时间：
2011-09
影响因子：
5.3
通讯作者：
Zhou C
中科院分区：
文献类型：
--
作者：
Hu X;Li T;Zhang C;Liu Y;Xu M;Wang W;Jia Z;Ma K;Zhang Y;Zhou C
心脏对多种刺激的反应性肥大具有重要的生理和病理意义。GATA 4在心肌肥大期间充当若干信号传导途径的核整合剂。据报道，Sp1和Sp3也参与了这一过程。然而，GATA 4作为介体整合这些普遍表达的转录因子的机制知之甚少。我们发现，GATA 4和Sp1的表达在压力超负荷肥大大鼠模型的心肌中上调，以及在苯肾上腺素诱导的（PE诱导的）新生心肌细胞肥大生长中上调。GST pull-down实验证明GATA 4在体外可以与Sp1相互作用。 因此，我们提出GATA 4与Sp1合作调节ANF表达，因为其再激活与肥大密切相关。进一步的研究表明，GATA 4可以通过直接相互作用与Sp1协同激活ANF启动子。相反，Sp3表现出拮抗作用，并且Sp3的过表达抑制了Sp1和GATA 4之间的转录协同作用。我们还发现，Sp1单独可以激活心肌细胞中的心钠素启动子，而Sp3对心钠素表达产生负面影响。生物信息学分析揭示了ANF启动子上新的Sp结合位点。在苯肾上腺素介导的肥大过程中，ANF启动子上GATA 4和Sp1的募集增强，而Sp3的募集减少。ERK 1/2激酶对GATA 4的磷酸化可增强GATA 4与Sp1之间的亲和力。因此，我们的研究结果揭示了GATA 4和Sp1在调节ANF表达中的关键相互作用，表明它们参与了心脏肥大。
Cardiac hypertrophy in response to multiple stimuli has important physiological and pathological significances. GATA4 serves as a nuclear integrator of several signalling pathways during cardiac hypertrophy. Sp1 and Sp3 are also reported to be involved in this process. However, the mechanism by which GATA4 acts as a mediator, integrating these ubiquitously expressed transcriptional factors, is poorly understood. We found that the expression of GATA4 and Sp1 was up‐regulated in the myocardium of a pressure overload hypertrophy rat model, as well in phenylephrine‐induced (PE‐induced) hypertrophic growth of neonatal cardiomyocytes. GST pull‐down assays demonstrated that GATA4 could interact with Sp1 in vitro. Therefore, we proposed that GATA4 cooperates with Sp1 in regulating ANF expression, as its reactivation is closely linked with hypertrophy. Further studies demonstrated that GATA4 could activate the ANF promoter synergistically with Sp1 through direct interaction. In contrast, Sp3 exhibited antagonistic function, and overexpression of Sp3 repressed the transcriptional synergy between Sp1 and GATA4. We also found that Sp1 alone could activate the ANF promoter in cardiomyocytes, whereas Sp3 exerted negative effects on ANF expression. Bioinformatics analysis revealed novel Sp‐binding sites on the ANF promoter. The recruitment of GATA4 and Sp1 on the ANF promoter was enhanced during phenylephrine‐mediated hypertrophy, whereas the recruitment of Sp3 was reduced. The phosphorylation of GATA4 by ERK1/2 kinase could enhance the affinity between GATA4 and Sp1. Thus, our findings revealed the critical interaction of GATA4 and Sp1 in modulating ANF expression, indicating their involvement in cardiac hypertrophy.
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影响因子：
--
作者：
Flück, CE;Miller, WL
通讯作者：
Miller, WL
影响因子：
5.6
作者：
Fandos, C;Sánchez-Feutrie, M;Zorzano, A
通讯作者：
Zorzano, A
影响因子：
2.9
作者：
Li, L;He, SH;Davie, JR
通讯作者：
Davie, JR
影响因子：
4.8
作者：
Sepulveda, JL;Vlahopoulos, S;Schwartz, RJ
通讯作者：
Schwartz, RJ
影响因子：
4.8
作者：
Chandrasekar, B;Mummidi, S;Nemer, M
通讯作者：
Nemer, M