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 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.
Matsuda
T
T
Department of Immunology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. tmatsuda@ms.toyama-mpu.ac.jp
Yamamoto
T
T
Muraguchi
A
A
Saatcioglu
F
F
D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta