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Título

p38 MAPK down-regulates fibulin 3 expression through methylation of gene regulatory sequences: role in migration and invasion

AutorArechederra, María; Gutiérrez-Uzquiza, Álvaro; Cerezo-Guisado, María Isabel; Ortiz-Rivero, Sara; Cuenda, Ana; Guerrero Arroyo, María del Carmen; Porras, Almudena
Palabras claveCancer biology, Cell signaling, Invasion, Migration, p38 MAPK, Fibulin 3
Fecha de publicación2015
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJournal of Biological Chemistry 290(7): 4383-4397 (2015)
Resumenp38 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. p38αhas a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by theDNAmethylase, 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.
URIhttp://hdl.handle.net/10261/135695
DOI10.1074/jbc.M114.582239
Identificadoresdoi: 10.1074/jbc.M114.582239
e-issn: 1083-351X
issn: 0021-9258
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