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

Transforming growth factor-beta (TGF-beta) plays central roles in embryonic development, organogenesis, and physiologic connective tissue remodeling d uring wound healing and tissue repair as well as in carcinogenesis. Estroge ns have key roles in a variety of biological events, such as the developmen t and maintenance of female reproductive organs and bone and lipid metaboli sm. Previous studies demonstrated that estrogens suppress TGF-beta -induced gene expression, such as type IV collagen in kidney mesangial cells. Howev er, the molecular mechanisms that mediate this antagonistic effect are unkn own. To elucidate the mechanisms of cross-talk between TGF-beta and estroge n receptor (ER) signaling pathways, we reconstituted TGF-beta and ER signal ing in human kidney carcinoma cells. Here we demonstrate that TGF-beta -ind uced activation of Sma and MAD-related protein 3 (Smad3) activity, one of t he major intracellular transducers of TGF-beta signaling, was suppressed by ER, whereas ER-mediated transcriptional activation was enhanced by TGF-bet a signaling. We provide evidence that this two-way cross-talk between the e strogen and TGF-beta signaling pathways was the result of direct physical i nteractions between Smad3 and ER. These findings have implications for a va riety of disease states, such as the pathophysiology of kidney function, at herosclerosis, and breast cancer.