Soluble form of the ST2 gene product exhibits growth promoting activity in NIH-3T3 cells

Abstract

The ST2 gene is induced in murine fibroblast cells at the start of cell proliferation. Although IL-33 has been identified as a ligand for one of the two major gene products of ST2 – namely, the transmembrane receptor form ST2L – prompting immunological research on inflammation, the roles of the ST2 gene products in cell proliferation remain to be elucidated.Using a cell proliferation assay system with NIH-3T3 cells, a normal murine fibroblast cell line, we found that treatment with recombinant ST2 caused an acceleration of cell proliferation, suggesting that ST2 acts in an autocrine/paracrine fashion. Strikingly, shRNA-induced knockdown of both ST2 gene products, ST2 and ST2L, reduced cell proliferation. This effect was effectively canceled by the expression of shRNA-resistant ST2, but not shRNA-resistant ST2L.The novel enhancement of cell proliferation by ST2 appears to involve positive feedback. Since the ST2 level is increased in various diseases involving inflammation, future investigations into the role of ST2 gene products in relation to various diseases, including malignancies, may be warranted.

ST2 gene products critically contribute to cellular transformation caused by an oncogenic Ras mutant

“…On the other hand, we already reported that ST2L was dispensable for the cellular transformation [24] . Taking these observations together, it was suggested that ST2 more critically contributed to cellular transformation than ST2L, and this is well fit with our previous report [25] .…”

“…We also found that the knockdown of ST2 gene products slowed down cell proliferation [25] . To determine whether ST2 gene products might positively regulate cell cycle progression, we silenced the expression of ST2 gene products in NIH-3T3 cells using sh-RNA and examined its effects on cell cycle progression from G 0 to G 2 /M phase.…”

“…8 C). In the previous report [25] , we showed that the addition of recombinant ST2 exhibited no effect on cell cycle progression. In the current study, we utilized the different experimental condition, in which endogenous ST2 gene products were knocked down by sh-RNA, and finally could observe the functional involvement of endogenous ST2/ST2L, probably ST2 in the cell cycle progression.…”

“…The action of NF-HEV seems to be independent of ST2/ST2L, however it is unclear how ST2/ST2L behave in the cellular transformation induced by oncogenic Ras. We already understand that ST2 but not ST2L contributes to cell proliferation of murine untransformed fibroblasts [25] . However, it is still unclear whether ST2/ST2L harbor the functional importance for the cellular transformation, and if so, what is the significance of ST2/ST2L for the cellular transformation.…”

STAT3 and ERK pathways are involved in cell growth stimulation of the ST2/IL1RL1 promoter

“…On the other hand, it was also reported that the IL-33/ST2L signaling axis exhibits an antitumor function [32,33], suggesting that the functional direction of ST2 gene products seems to depend on the environmental conditions such as the tumor cell type. Additionally, we reported recently the functional importance of ST2 for cell cycle progression provoked by serum stimulation [34], and our study suggested that ST2 seems to be involved in cell proliferation of not only tumor cells but also normal fibroblasts. These observations emphasized the importance of investigation of the mechanism by which the ST2 promoter is regulated.…”