Cross-talk between transforming growth factor-beta and estrogen receptor signaling through Smad3.

Tadashi Matsuda,Fahri Saatcioglu,Atsushi Muraguchi,Tetsuya Yamamoto

doi:10.1074/jbc.m105316200

Abstract

Transforming growth factor-beta (TGF-beta) plays central roles in embryonic development, organogenesis, and physiologic connective tissue remodeling during wound healing and tissue repair as well as in carcinogenesis. Estrogens have key roles in a variety of biological events, such as the development and maintenance of female reproductive organs and bone and lipid metabolism. Previous studies demonstrated that estrogens suppress TGF-beta-induced gene expression, such as type IV collagen in kidney mesangial cells. However, the molecular mechanisms that mediate this antagonistic effect are unknown. To elucidate the mechanisms of cross-talk between TGF-beta and estrogen receptor (ER) signaling pathways, we reconstituted TGF-beta and ER signaling in human kidney carcinoma cells. Here we demonstrate that TGF-beta-induced activation of Sma and MAD-related protein 3 (Smad3) activity, one of the major intracellular transducers of TGF-beta signaling, was suppressed by ER, whereas ER-mediated transcriptional activation was enhanced by TGF-beta signaling. We provide evidence that this two-way cross-talk between the estrogen and TGF-beta signaling pathways was the result of direct physical interactions between Smad3 and ER. These findings have implications for a variety of disease states, such as the pathophysiology of kidney function, atherosclerosis, and breast cancer.

Highlights

Transforming growth factor-␤ (TGF-␤) plays central roles in embryonic development, organogenesis, and physiologic connective tissue remodeling during wound healing and tissue repair as well as in carcinogenesis
We demonstrate that TGF-␤-induced activation of Sma and MAD-related protein 3 (Smad3) activity, one of the major intracellular transducers of TGF-␤ signaling, was suppressed by estrogen receptor (ER), whereas ER-mediated transcriptional activation was enhanced by TGF-␤ signaling
We examined the effect of estrogens on TGF-␤ signaling in this model system. 293T cells were transfected with an expression vector for ER␣, T␤R-I(T204D), and p3TP-LUC and were either left untreated or stimulated with E2

Summary

Introduction

Transforming growth factor-␤ (TGF-␤) plays central roles in embryonic development, organogenesis, and physiologic connective tissue remodeling during wound healing and tissue repair as well as in carcinogenesis. Estrogens Inhibit TGF-␤ Signaling in 293T Cells—To examine the molecular basis of the cross-talk between TGF-␤ and ER signaling pathways, we performed the transient transfection assay using human embryonic kidney carcinoma cell line 293T. 293T cells were transfected with an expression vector for ER␣, T␤R-I(T204D), and p3TP-LUC and were either left untreated or stimulated with E2.

Results

Conclusion