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

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.

• Authors: T Matsuda, T Yamamoto, A Muraguchi, F Saatcioglu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 46 Pg. 42908-14 (Nov 16 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11555647 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens
• Receptors, Estrogen
• Recombinant Proteins
• SMAD3 protein, human
• Smad3 Protein
• Trans-Activators
• Transforming Growth Factor beta

Topics

• Blotting, Northern
• DNA-Binding Proteins (metabolism)
• Enzyme Activation
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens (pharmacology)
• Humans
• Immunoblotting
• Kidney Neoplasms (metabolism)
• Precipitin Tests
• Protein Binding
• Protein Structure, Tertiary
• Receptors, Estrogen (chemistry, metabolism)
• Recombinant Proteins (metabolism)
• Signal Transduction
• Smad3 Protein
• Trans-Activators (metabolism)
• Transforming Growth Factor beta (chemistry, metabolism)
• Tumor Cells, Cultured