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RhoA–ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells Ordóñez Morán, Paloma Larriba, María Jesús García Palmer, Héctor Valero, Ruth Ana Barbáchano Becerril, Antonio Duñach Masjuan, Mireia García de Herreros, Antonio Villalobos Jorge, Carlos Berciano, María Teresa Lafarga Coscojuela, Miguel Ángel Muñoz Terol, Alberto Colorectal cancer Cáncer colorrectal Vitamin D Vitamina D Gene expression Expresión génica Phenotype Fenotipo Producción Científica 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. Ministerio de Ciencia, Innovación y Universidades (grant SAF2007-60341) Ministerio de Sanidad, Consumo y Bienestar Social (grant RD06/0020/0009) Comunidad de Madrid (grant S-GEN-0266/2006) Unión Europea (grant MRTN-CT-2005-019496) 2021-01-19T13:31:14Z 2021-01-19T13:31:14Z 2008 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Journal of Cell Biology, 2008, vol. 183, n. 4. p. 697-710 1540-8140 http://uvadoc.uva.es/handle/10324/45078 10.1083/jcb.200803020 eng https://rupress.org/jcb/article/183/4/697/45660/RhoA-ROCK-and-p38MAPK-MSK1-mediate-vitamin-D Attribution-NonCommercial-NoDerivs 3.0 Unported info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/3.0/ © 2008 Rockefeller University Press application/pdf Rockefeller University Press https://uvadoc.uva.es/bitstream/10324/45078/4/RhoA-ROCK.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by-nc-nd/3.0/ UVaDOC. Repositorio Documental de la Universidad de Valladolid http://uvadoc.uva.es/handle/10324/45078