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

María Arechederra1, Neibla Priego1, Ana Vázquez-Carballo1

  • 1From the Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.

The Journal of Biological Chemistry
|December 31, 2014
PubMed

Insights

p38 MAPKs regulate cell migration and invasion by controlling fibulin 3 expression. This study reveals how p38 kinases impact fibulin 3 levels and function, influencing tumor growth and metastasis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • p38 Mitogen-Activated Protein Kinases (MAPKs) are key regulators of cell migration and invasion.
  • The precise mechanisms by which p38 MAPKs control these processes are not fully understood.
  • Fibulin 3 has been identified as a gene involved in migration, invasion, and tumorigenesis, and is regulated by p38α.

Purpose of the Study:

  • To elucidate the detailed mechanisms by which p38 MAPKs regulate fibulin 3 expression.
  • To investigate the role of fibulin 3 in cell migration, invasion, and tumor growth.
  • To explore the interplay between p38 MAPKs and fibulin 3 in different cellular contexts.

Main Methods:

  • Analysis of fibulin 3 gene expression regulation by p38 MAPKs (p38α, p38γ, p38δ).
  • Investigation of DNA methylation in fibulin 3 regulatory sequences.
  • Assessment of DNMT3A and HuR involvement in the p38α-mediated regulation.
  • Functional studies involving fibulin 3 knockdown in MEFs and HCT116 cells.
  • In vitro and in vivo tumor growth assays.

Main Results:

  • p38α, p38γ, and p38δ were found to down-regulate fibulin 3 expression, with p38α having a more pronounced effect.
  • p38α mediates fibulin 3 down-regulation via hypermethylation of gene regulatory sequences, involving DNMT3A stabilization by HuR.
  • Fibulin 3 inhibits migration and invasion in MEFs, partly through p38α/β inhibition.
  • In HCT116 cells, Fibulin 3 promotes migration and invasion dependent on p38α/β activation and enhances tumor growth.
  • A negative feedback loop where p38α limits fibulin 3 expression was observed.

Conclusions:

  • p38 MAPKs differentially regulate fibulin 3 expression through epigenetic mechanisms (methylation) and mRNA stabilization.
  • Fibulin 3's role in migration and invasion is context-dependent, acting as an inhibitor in MEFs and a promoter in HCT116 cells.
  • p38α plays a complex role, inhibiting fibulin 3 expression while promoting tumor growth, suggesting a regulatory feedback mechanism crucial for tumorigenesis.
Keywords:
cancer biologycell signalingfibulin 3invasionmigrationp38 MAPK

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