RT Journal Article
T1 p38 MAPK Down-regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences
A1 Arechederra, María
A1 Priego, Neibla
A1 Vázquez-Carballo, Ana
A1 Sequera Hurtado, Celia
A1 Gutiérrez Uzquiza, Álvaro
A1 Cerezo-Guisado, María Isabel
A1 Ortiz-Rivero, Sara
A1 Roncero Romero, Cesáreo
A1 Cuenda, Ana
A1 Guerrero, Carmen
A1 Porras Gallo, María Almudena
AB 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/  inhibition. Hence, p38 promigratory/invasive effect might be, at least in part, mediated by fibulin 3 downregulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38 and/or p38  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 sametime, p38 limits fibulin 3 expression, which might represent a negative feed-back loop.
PB Elsevier
SN 0021-9258
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/115686
UL https://hdl.handle.net/20.500.14352/115686
LA eng
NO Arechederra, María, et al. «P38 MAPK Down-Regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences». Journal of Biological Chemistry, vol. 290, n.o 7, febrero de 2015, pp. 4383-97. https://doi.org/10.1074/jbc.M114.582239.
NO Junta de Castilla y León
NO European Commission
NO Ministerio de Economía y Competitividad (España)
NO Ministerio de Educación (España)
DS Docta Complutense
RD 8 abr 2025