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p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway

Lijian Hui1, Latifa Bakiri, Andreas Mairhorfer

  • 1Research Institute of Molecular Pathology, A-1030 Vienna, Austria.

Nature Genetics
|May 1, 2007
PubMed

Insights

Mitogen-activated protein kinase (MAPK) p38alpha normally suppresses cell growth. Its absence boosts proliferation via the JNK-c-Jun pathway, promoting liver cancer development in mice.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The mitogen-activated protein kinase (MAPK) p38alpha is a key regulator of inflammatory responses and cell proliferation.
  • Understanding p38alpha's role is crucial for developing targeted therapies for diseases involving uncontrolled cell growth.

Purpose of the Study:

  • To investigate the function of p38alpha (encoded by Mapk14) in postnatal development and liver tumorigenesis.
  • To elucidate the molecular mechanisms by which p38alpha influences cell proliferation and cancer progression.

Main Methods:

  • Utilized conditional Mapk14 knockout mice to delete p38alpha specifically in embryonic or liver cells.
  • Analyzed fetal development, cell proliferation rates in hematopoietic cells and fibroblasts, and liver cancer development.
  • Assessed the involvement of the c-Jun N-terminal kinase (JNK)-c-Jun pathway through genetic inactivation.

Main Results:

  • Embryonic deletion of Mapk14 led to perinatal lethality, likely due to lung dysfunction.
  • p38alpha-deficient cells exhibited increased proliferation, driven by sustained JNK-c-Jun pathway activation.
  • Liver-specific Mapk14 deletion enhanced hepatocyte proliferation and chemical-induced liver tumor development.
  • Inactivating JNK or c-Jun reversed the hyperproliferation in Mapk14-deficient cells and tumor cells.

Conclusions:

  • p38alpha acts as a negative regulator of cell proliferation by antagonizing the JNK-c-Jun pathway.
  • This inhibitory mechanism is operative in multiple cell types and is relevant to liver cancer development.
  • Targeting the p38alpha-JNK-c-Jun axis may offer therapeutic strategies for cancers characterized by aberrant proliferation.

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