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oai:gredos.usal.es:10366/1634392025-04-30T20:50:50Zcom_10366_4613com_10366_4576com_10366_3823col_10366_4616

Arechederra, María Priego, Neibla Vázquez-Carballo, Ana Sequera, Celia Gutiérrez-Uzquiza, Álvaro Cerezo-Guisado, María Isabel Ortiz-Rivero, Sara Roncero Maíllo, César Cuenda, Ana Guerrero Arroyo, María Carmen Porras, Almudena 2025-02-03T09:44:07Z 2025-02-03T09:44:07Z 2015 Arechederra, M., Priego, N., Vázquez-Carballo, A., Sequera, C., Gutiérrez-Uzquiza, Á., Cerezo-Guisado, M. I., Ortiz-Rivero, S., Roncero, C., Cuenda, A., Guerrero, C., y Porras, A. (2015). P38 mapk down-regulates fibulin 3 expression through methylation of gene regulatory sequences. Journal of Biological Chemistry, 290(7), 4383-4397. https://doi.org/10.1074/jbc.M114.582239 0021-9258 http://hdl.handle.net/10366/163439 10.1074/jbc.M114.582239 [EN]P38 MAPKs regulate migration and invasion. However, the mechanisms involved are only partially known. We had previously identified fibulin 3, which plays a role in migration, invasion, and tumorigenesis, as a gene regulated by p38α. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38α, p38γ, and p38δ down-regulate fibulin 3 expression. p38α has a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by the DNA methylase, DNMT3A, which is down-regulated in cells lacking p38α, but once re-introduced represses Fibulin 3 expression. p38α through HuR stabilizes dnmt3a mRNA leading to an increase in DNMT3A protein levels. Moreover, by knocking-down fibulin 3, we have found that Fibulin 3 inhibits migration and invasion in MEFs by mechanisms involving p38α/β inhibition. Hence, p38α pro-migratory/invasive effect might be, at least in part, mediated by fibulin 3 down-regulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38α and/or p38β activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38α, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38α limits fibulin 3 expression, which might represent a negative feed-back loop. eng Elsevier Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess cancer biology cell signaling invasion migration Medical Oncology Cells p38 Mitogen-Activated Protein Kinases HCT116 Cells oncología médica células células HCT116 proteína cinasas p38 activadas por mitógenos p38 MAPK Down-regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion https://doi.org/10.1074/jbc.M114.582239 Journal of Biological Chemistry 290 7 4383 4397