Abstract
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.
Highlights
The ST2 gene was originally identified as a primary responsive gene induced by stimulation with growth factors and by oncogenic stress
We clarified that activation of the ST2 promoter by either growth stimulation or oncogenic Ras was suppressed by the inhibitors for STAT3 and extracellular signal-regulated kinase (ERK) pathways
From performed luciferase reporter gene assays, we observed that the proximal promoter region but not the distal promoter region was activated in serum-stimulated human fibroblast TM12 cells (Fig. 1B)
Summary
The ST2 gene was originally identified as a primary responsive gene induced by stimulation with growth factors and by oncogenic stress. Our observations strongly suggest the importance of STAT family and ERK pathways for the induction of ST2 gene products by cell growth stimulation. ST2 (IL1RL1, called T1) was originally identified as a primary responsive gene that was highly induced by growth stimulation and oncogenic Ras-induced signaling in quiescent murine fibroblasts [1,2]. In the case of hematopoietic cells, both the distal and proximal promoters were utilized for the expression of ST2 and ST2L [17]. These observations suggested that ST2 promoter usage depends on the cell type. It has not been clarified yet how the proximal promoter is regulated, because various promoter elements have been identified in the proximal promoter of the ST2 gene [20,21]
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