PT - JOURNAL ARTICLE AU - Hong Jin Lee AU - Andrew Wislocki AU - Catherine Goodman AU - Yan Ji AU - Rongrong Ge AU - Hubert Maehr AU - Milan Uskokovic AU - Michael Reiss AU - Nanjoo Suh TI - A Novel Vitamin D Derivative Activates Bone Morphogenetic Protein Signaling in MCF10 Breast Epithelial Cells AID - 10.1124/mol.105.022079 DP - 2006 Jun 01 TA - Molecular Pharmacology PG - 1840--1848 VI - 69 IP - 6 4099 - http://molpharm.aspetjournals.org/content/69/6/1840.short 4100 - http://molpharm.aspetjournals.org/content/69/6/1840.full SO - Mol Pharmacol2006 Jun 01; 69 AB - We investigated the action of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], a novel Gemini vitamin D3 analog Ro-438-3582 [1α,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluorocholecalciferol (Ro3582)], and a classic vitamin D3 analog Ro-26-2198 [1α,25-dihydroxy-16,23(Z)-diene-26,27-hexafluoro-19-nor-cholecalciferol (Ro2198)] in modulating the transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) system in MCF10 immortalized breast epithelial cells. We found that 1α,25(OH)2D3, Ro3582, and Ro2198 all enhanced BMP/Smad signaling by increasing the phosphorylation of receptor-regulated Smads. Ro3582 was more active than Ro2198, but both were considerably more active than 1α,25(OH)2D3. Ro3582 enhanced BMP/Smad signaling by 1) inducing the phosphorylation of receptor-regulated Smads (Smad1/5), 2) increasing the accumulation of phosphorylated Smad1/5 in the nucleus, and 3) activating BMP-mediated transcription in MCF10 breast epithelial cells. Furthermore, Ro3582 induced the synthesis of BMP-2 and BMP-6 mRNA and protein, and the expression of Smad6 mRNA in MCF10 breast epithelial cells was inhibited by Ro3582. The induction of phospho-Smad1/5 by Ro3582 was inhibited by treatment with the BMP antagonist Noggin, whereas neutralizing antibody to TGF-β did not block the induction of phospho-Smad1/5 by Ro3582. Treatment with Noggin also blocked the effect of Ro3582 on nuclear accumulation of phospho-Smad1/5 and the induction of BMP-2 and BMP-6 mRNA synthesis. These results indicate that the activation of BMP/Smad signaling by the Gemini vitamin D3 analog Ro3582 may be through the production of BMP ligands, including BMP-2 and BMP-6, and/or down-regulation of the inhibitory Smad6. This is the first report to show that 1α,25(OH)2D3 and its derivatives activate BMP/Smad-specific signaling in human breast epithelial cells.