Tago Kenji, Ohta Satoshi, Funakoshi-Tago Megumi, Aoki-Ohmura Chihiro, Matsugi Jitsuhiro, Tominaga Shin-Ichi, Yanagisawa Ken
Division of Structural Biochemistry Jichi Medical University Shimotsuke Tochigi Japan.
Department of Hygienic Chemistry Faculty of Pharmacy Keio University Minato-ku Tokyo Japan.
FEBS Open Bio. 2017 Jan 19;7(2):293-302. doi: 10.1002/2211-5463.12192. eCollection 2017 Feb.
The ST2 gene was originally identified as a primary responsive gene induced by stimulation with growth factors and by oncogenic stress. The ST2 gene harbors two distinct promoters - a distal promoter and a proximal promoter. In this study, we identified a novel type of serum-responsive element in the ST2 proximal promoter using reporter gene analysis; this element includes a possible responsive element for STAT family proteins. Indeed, enforced expression of constitutively active STAT3 activated this promoter element and induced the expression of ST2 gene products. Furthermore, an oncogenic Ras (G12V) mutant also caused the expression of ST2 gene products by utilizing the proximal promoter. We also clarified that activation of the ST2 promoter by either growth stimulation or oncogenic Ras was suppressed by the inhibitors for STAT3 and ERK pathways. Our observations strongly suggest the importance of STAT family and ERK pathways for the induction of ST2 gene products by cell growth stimulation.
ST2基因最初被鉴定为受生长因子刺激和致癌应激诱导的主要反应基因。ST2基因有两个不同的启动子——一个远端启动子和一个近端启动子。在本研究中，我们通过报告基因分析在ST2近端启动子中鉴定出一种新型血清反应元件；该元件包括一个可能的STAT家族蛋白反应元件。事实上，组成型活性STAT3的强制表达激活了该启动子元件并诱导了ST2基因产物的表达。此外，致癌性Ras（G12V）突变体也通过利用近端启动子导致ST2基因产物的表达。我们还阐明，STAT3和ERK通路的抑制剂可抑制生长刺激或致癌性Ras对ST2启动子的激活。我们的观察结果强烈表明，STAT家族和ERK通路对于细胞生长刺激诱导ST2基因产物具有重要意义。
