Doriguzzi Angelina, Haigl Barbara, Gsur Andrea, Sutterlüty-Fall Hedwig
Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Int J Biochem Cell Biol. 2015 Jul;64:220-8. doi: 10.1016/j.biocel.2015.04.017. Epub 2015 May 6.
Sprouty proteins control length and intensity of the intracellular signal transduction cascade activated by mitogens in the cellular environment. As part of a negative feedback loop, their expression is supposed to be elevated by the same factors. In this report, Sprouty4 expression in response to serum and the underlying regulatory mechanisms were investigated. We verified that Sprouty4 expression is activated by serum addition in all tested cells independent of their origin. Strict correlation between Sprouty4 protein levels and promoter activity indicates mainly transcriptional regulation of Sprouty4 serum-responsiveness. Induction of the mitogen-activated protein kinase pathway is required for Sprouty4 promoter activation in the presence of serum. Nonetheless, signal transduction via this pathway is not sufficient to fully induce the Sprouty4 promoter. Instead, deletion and mutation analysis identified two annotated Specific protein 1 binding sites as the critical cis-elements responsible for conferring the serum induction of the promoter. Corroborating, repressed Specific protein 1 activity or levels result in constitutive lowered transcriptional activity of the Sprouty4 promoter. These data demonstrate that Specific protein 1 plays a crucial role in the regulation of Sprouty4 in response to serum.
Sprouty蛋白在细胞环境中控制由促细胞分裂剂激活的细胞内信号转导级联反应的长度和强度。作为负反馈回路的一部分，其表达应该会被相同的因子上调。在本报告中，研究了Sprouty4对血清的反应及其潜在的调控机制。我们证实，在所有测试细胞中，无论其来源如何，添加血清均可激活Sprouty4的表达。Sprouty4蛋白水平与启动子活性之间的严格相关性表明，Sprouty4对血清的反应主要受转录调控。在有血清存在的情况下，丝裂原活化蛋白激酶途径的诱导是Sprouty4启动子激活所必需的。然而，通过该途径的信号转导不足以完全诱导Sprouty4启动子。相反，缺失和突变分析确定了两个注释的特异性蛋白1结合位点，作为赋予启动子血清诱导作用的关键顺式元件。相应地，特异性蛋白1活性或水平的抑制会导致Sprouty4启动子的转录活性持续降低。这些数据表明，特异性蛋白1在血清刺激下对Sprouty4的调控中起关键作用。
