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Published online
doi:10.1083/jcb.200803020
The Journal of Cell Biology, Vol. 183, No. 4, 697-710
The Rockefeller University Press, 0021-9525 $30.00
© Ordóñez-Morán et al.
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Article

RhoA–ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells



Paloma Ordóñez-Morán1, María Jesús Larriba1, Héctor G. Pálmer1, Ruth A. Valero2, Antonio Barbáchano1, Mireia Duñach3, Antonio García de Herreros4, Carlos Villalobos2, María Teresa Berciano5, Miguel Lafarga5, and Alberto Muñoz1

1 Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, E-28029 Madrid, Spain
2 Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, E-47003 Valladolid, Spain
3 Facultad de Medicina, Universidad Autónoma de Barcelona, E-08193 Bellaterra, Spain
4 Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain
5 Departamento de Anatomía y Biología Celular, Unidad de Biomedicina, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria, E-39011 Santander, Spain

Correspondence to amunoz{at}iib.uam.es

The active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proliferation and promotes differentiation of colon cancer cells through the activation of vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Additionally, 1,25(OH)2D3 has several nongenomic effects of uncertain relevance. We show that 1,25(OH)2D3 induces a transcription-independent Ca2+ influx and activation of RhoA–Rho-associated coiled kinase (ROCK). This requires VDR and is followed by activation of the p38 mitogen-activated protein kinase (p38MAPK) and mitogen- and stress-activated kinase 1 (MSK1). As shown by the use of chemical inhibitors, dominant-negative mutants and small interfering RNA, RhoA–ROCK, and p38MAPK-MSK1 activation is necessary for the induction of CDH1/E-cadherin, CYP24, and other genes and of an adhesive phenotype by 1,25(OH)2D3. RhoA–ROCK and MSK1 are also required for the inhibition of Wnt–β-catenin pathway and cell proliferation. Thus, the action of 1,25(OH)2D3 on colon carcinoma cells depends on the dual action of VDR as a transcription factor and a nongenomic activator of RhoA–ROCK and p38MAPK-MSK1.

H.G. Pálmer's present address is Institut de Recerca Vall d'Hebron, E-08035 Barcelona, Spain.

Abbreviations used in this paper: 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; ATF1, activating transcription factor 1; CREB, cAMP response element-binding protein; DKK-1, dickkopf-1; DRB, 5,6-dichlorobenzimidazole riboside; ERK, extracellular signal-regulated kinase; MSK1, mitogen- and stress-activated kinase 1; OCN, osteocalcin; OPN, osteopontin; qRT-PCR, quantitative RT-PCR; PRK2, protein-related kinase 2; ROCK, Rho-associated coiled kinase; shRNA, small hairpin RNA; TCF, T cell factor; VDR, vitamin D receptor; WB, Western blotting.

© 2008 Ordóñez-Morán et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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