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Positive and negative modulation of vitamin D receptor function by transforming growth factor-beta signaling through
Y Yanagi1, M Suzawa, M Kawabata
1Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0034, Japan.
Abstract:
Several lines of experiments demonstrated the interplay between the transforming growth factor-beta (TGF-beta) and vitamin D signaling pathways. Recently, we found that Smad3, a downstream component of the TGF-beta 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-beta/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 studies in 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-beta 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.
Insights
Transforming growth factor-beta (TGF-beta) and vitamin D signaling pathways interact. Inhibitory Smad7 blocks Smad3
Area of Science:
- Molecular Biology
- Cell Signaling
- Endocrinology
Background:
- Transforming growth factor-beta (TGF-beta) and vitamin D signaling pathways are crucial in cellular processes.
- Smad3 acts as a coactivator, enhancing vitamin D receptor (VDR) function.
- Inhibitory Smads (Smad6, Smad7) negatively regulate TGF-beta signaling.
Purpose of the Study:
- To investigate the role of Smad6 and Smad7 in modulating the Smad3-mediated potentiation of VDR function.
- To elucidate the mechanism by which inhibitory Smads affect the interaction between TGF-beta and vitamin D signaling.
Main Methods:
- In vivo and in vitro interaction studies.
- Assays to evaluate VDR transactivation potentiation.
- Analysis of Smad6 and Smad7 effects on VDR-Smad3 complex formation.
Main Results:
- Smad7, but not Smad6, abrogated the Smad3-mediated potentiation of VDR function.
- Smad7 inhibited the formation of the VDR-Smad3 complex.
- Smad6 did not affect VDR-Smad3 complex formation or VDR potentiation.
Conclusions:
- Smad7 plays a critical role in negatively regulating the interplay between TGF-beta and vitamin D signaling.
- The interaction between TGF-beta and vitamin D pathways is mediated by Smad proteins, influencing VDR transactivation.
- Smad proteins differentially modulate VDR function, with Smad3 acting as a positive regulator and Smad7 as a negative regulator.