Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha.

Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha. Research Abstract Details 

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Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha. Abstract Text:

Hong Jin Lee,Yan Ji,Shiby Paul,Hubert Maehr,Milan Uskokovic,Nanjoo Suh,Hong Jin Lee,Yan Ji,Shiby Paul,Hubert Maehr,Milan Uskokovic,Nanjoo Suh,

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta 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 D(3) analogue, Ro-438-3582 [Ro3582; 1 alpha,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 alpha, but not PKC epsilon, PKC delta or PKC zeta isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKC alpha 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 alpha to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKC alpha and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKC alpha pathway in breast epithelial cells.

Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha. Publishing Authors By Initials

HJ Lee,Y Ji,S Paul,H Maehr,M Uskokovic,N Suh,HJ Lee,Y Ji,S Paul,H Maehr,M Uskokovic,N Suh,

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Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 67

Page Numbers: 11840-7

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 15

MONTH: Dec

YEAR: 2007

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for Activation of bone morphogenetic protein signaling by a Gemini vitamin D3 analogue is mediated by Ras/protein kinase C alpha.

AFFILIATION: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.

Country: United States

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MEDLINETA: Cancer Res

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