Wang Jun, Paradis Pierre, Aries Anne, Komati Hiba, Lefebvre Chantal, Wang Hao, Nemer Mona
Unité de Recherche en Développement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, 110, Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
Mol Cell Biol. 2005 Nov;25(22):9829-44. doi: 10.1128/MCB.25.22.9829-9844.2005.
Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.
血管紧张素II（AII）是一种强效血管活性激素，通过G蛋白偶联受体作用于多个器官，并引发细胞特异性反应。在心脏水平，AII刺激会改变基因转录并导致心肌细胞肥大。在此过程中，众多细胞内信号通路被激活；然而，这些通路中哪些直接将受体激活与转录调控联系起来仍不明确。我们使用心钠素（ANF）基因（NPPA）作为标志物来阐明参与AII转录反应的信号级联。我们发现ANF转录直接由AII 1型受体激活，且先于心肌细胞肥大的发展。这种反应定位于STAT和GATA结合位点，这两个元件在转录上协同作用，通过JAK-STAT和蛋白激酶C（PKC）-GATA-4途径介导信号传导。PKC磷酸化增强GATA-4与DNA的结合活性，STAT-1在功能和物理上与GATA-4相互作用，以协同激活AII和其他生长因子诱导型启动子。此外，GATA因子能够通过GATA结合位点将STAT蛋白募集到目标启动子，这些位点足以支持协同作用。因此，STAT蛋白可作为组织特异性转录因子的生长因子诱导型共激活因子。STAT和GATA蛋白之间的相互作用可能为理解细胞因子和生长因子信号传导的细胞特异性提供一个通用范例。
