This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, H. J. Articles by Suh, N. Search for Related Content PubMed PubMed Citation Articles by Lee, H. J. Articles by Suh, N.

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D₃ Analogue Is Mediated by Ras/Protein Kinase C

¹ Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey and ² The Cancer Institute of New Jersey, New Brunswick, New Jersey

Requests for reprints: Nanjoo Suh, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 226; Fax: 732-445-0687; E-mail: nsuh{at}rci.rutgers.edu.

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-β superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D₃ analogue, Ro-438-3582 [Ro3582; 1,25-dihydroxy-20S,21(3-hydroxy-3-methylbutyl)-23-yne-26,27-hexafluorocholecalciferol], inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKC, but not PKC, PKC or PKC isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKC mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras–transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKC to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKC and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKC pathway in breast epithelial cells. [Cancer Res 2007;67(24):11840–7]

This article has been cited by other articles:

				H. J. Lee, S. Paul, N. Atalla, P. E. Thomas, X. Lin, I. Yang, B. Buckley, G. Lu, X. Zheng, Y.-R. Lou, et al. Gemini Vitamin D Analogues Inhibit Estrogen Receptor-Positive and Estrogen Receptor-Negative Mammary Tumorigenesis without Hypercalcemic Toxicity Cancer Prevention Research, November 1, 2008; 1(6): 476 - 484. [Abstract] [Full Text] [PDF]