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Positive and negative modulation of vitamin D receptor function by transforming growth factor-β signaling through Smad proteins.

Abstract Several lines of experiments demonstrated the interplay between the transforming growth factor-β (TGF-β) and vitamin D signaling pathways. Recently, we found that Smad3, a downstream component of the TGF-β signaling pathway, potentiates ligand-induced transactivation of vitamin D receptor (VDR) as a coactivator of VDR (Yanagisawa, J., Yanagi, Y., Masuhiro, Y., Suzawa, M., Watanabe, M., Kashiwagi, K., Toriyabe, T., Kawabata, M., Miyazono, K., and Kato, S. (1999) Science 283, 1317–1321). Here, we investigated the roles of inhibitory Smads, Smad6 and Smad7, which are negative regulators of the TGF-β/bone morphogenetic protein signaling pathway, on the Smad3-mediated potentiation of VDR function. We found that Smad7, but not Smad6, abrogates the Smad3-mediated VDR potentiation. Interaction studiesin vivo and in vitro showed that Smad7 inhibited the formation of the VDR-Smad3 complex, whereas Smad6 had no effect. Taken together, our results strongly suggest that the interplay between the TGF-β and vitamin D signaling pathways is, at least in part, mediated by the two classes of Smad proteins, which modulate VDR transactivation function both positively and negatively.