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ZAS3 accentuates transforming growth factor ? signaling in epithelial cells.

ABSTRACT: In mammals, the ZAS family of transcription factors activates or represses transcription depending on the cellular context. In the current study, we explored the interaction between ZAS3 and TGF?1 signaling in epithelial cells using HEK293 cells and the intestinal epithelial cell line, RIE-1. Endogenous ZAS3 expression was detected in each cell line and the small intestine of mice. Additionally, endogenous ZAS3 expression was increased in both whole cell and nuclear lysates by TGF?1 and in vivo in TGF?-overexpressing mice, indicating a potential interaction between ZAS3 and TGF?. ZAS3 transfection enhanced TGF?1 activation of a luciferase reporter in both HEK293 and RIE-1 cells. Analysis of truncated ZAS3 constructs revealed a 155 amino acid, N-terminal sequence between amino acids 106 and 261 that was required for enhancement of TGF?1-mediated transcription. Co-immunoprecipitation experiments with nuclear extracts from TGF?1-stimulated HEK293 cells revealed an association between ZAS3 and the Smad complex. Additionally, transfected ZAS3 decreased the association between the Smad complex and the TGF? transcriptional repressors Ski and SnoN, indicating a possible mechanism for the enhancement of transcription by exogenous ZAS3. These observations were confirmed by site-directed mutagenesis of ZAS domains homologous with Smad-interacting domains in Ski and SnoN. Finally, ZAS3 transfection enhanced the TGF?1-mediated induction of ?-smooth muscle actin in HEK293 cells, indicating that ZAS3 plays a functional role in TGF? signaling. In conclusion, we have identified an interaction between ZAS3 and Smad proteins that enhances TGF? signaling. Since TGF? signaling is primarily known as a negatively regulated pathway, the enhancement of signaling by ZAS3 has novel implications for understanding TGF? biology.

SUBMITTER: Yakovich AJ

PROVIDER: S-EPMC2967717 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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ZAS3 accentuates transforming growth factor β signaling in epithelial cells.

Yakovich Adam J AJ Jiang Bo B Allen Carl E CE Du Jianguo J Wu Lai-Chu LC Barnard John A JA

Cellular signalling 20100821 1

In mammals, the ZAS family of transcription factors activates or represses transcription depending on the cellular context. In the current study, we explored the interaction between ZAS3 and TGFβ1 signaling in epithelial cells using HEK293 cells and the intestinal epithelial cell line, RIE-1. Endogenous ZAS3 expression was detected in each cell line and the small intestine of mice. Additionally, endogenous ZAS3 expression was increased in both whole cell and nuclear lysates by TGFβ1 and in vivo ...[more]

PMID: 20732416

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Project description:Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors, and angiogenic factors. In previous studies, conditional deletion of the type II transforming growth factor-beta (TGF-beta) receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast-epithelial cell cotransplantation studies in mice, correlating with increased expression of hepatocyte growth factor (HGF). Here, we advance our findings to show that Tgfbr2(FspKO) fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by small interfering RNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion, correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the signal transducer and activator of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) signaling pathways by pharmacologic inhibition and small interfering RNA silencing revealed a cooperative interaction between the two pathways to regulate HGF-induced invasion, scattering, and motility of mammary tumor cells. Furthermore, whereas c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3 but not MAPK signaling in mammary carcinoma cells. These studies show a tumor-suppressive role for TGF-beta signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-beta signaling in mediating tumor-stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process.

Dataset Information

ZAS3 accentuates transforming growth factor ? signaling in epithelial cells.

Publications

ZAS3 accentuates transforming growth factor β signaling in epithelial cells.

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