Detalle Publicación


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

Autores: Arechederra Calderon, Maria; Priego, N. ; Vázquez-Carballo, A. ; Sequera, C. ; Gutierrez-Uzquiza, A.; Cerezo-Guisado, M.I.; Ortiz-Rivero, S. ; Roncero, C. ; Cuenda, A.; Guerrero, C. (Autor de correspondencia); Porras, A.
ISSN: 1083-351X
Volumen: 290
Número: 7
Páginas: 4383 - 4397
Fecha de publicación: 2015
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 p38¿. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38¿, p38¿, and p38¿ down-regulate fibulin 3 expression. p38¿ 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 p38¿, but once re-introduced represses Fibulin 3 expression. p38¿ 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 p38¿/ß inhibition. Hence, p38¿ 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 p38¿ and/or p38ß activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38¿, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38¿ limits fibulin 3 expression, which might represent a negative feed-back loop.