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Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell

Min Jung Kim1, Bum-Joon Park, Young-Sun Kang

  • 1National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.

Nature Genetics
|June 24, 2003
PubMed

Insights

p38 protein is crucial for lung development in mice. Its disruption leads to respiratory distress by affecting FUSE-binding protein and c-myc regulation, essential for cell differentiation.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • p38 protein is a scaffold in a macromolecular tRNA synthetase complex.
  • Genetic disruption of p38 in mice results in neonatal lethality.
  • Understanding the molecular basis of p38-related lethality is critical.

Purpose of the Study:

  • To investigate the molecular mechanisms causing neonatal lethality in p38-mutant mice.
  • To elucidate the role of p38 in lung differentiation and respiratory distress.
  • To identify novel functions of p38 in cellular signaling pathways.

Main Methods:

  • Analysis of p38-deficient mouse models exhibiting lung defects.
  • Investigation of protein-protein interactions between p38 and FUSE-binding protein (FBP).
  • Assessment of c-myc expression levels and its regulation by p38 and FBP.
  • Study of transforming growth factor-beta (TGF-beta) signaling in p38-mutant mice.

Main Results:

  • p38-deficient mice displayed significant defects in lung differentiation and respiratory distress syndrome.
  • p38 interacts with FBP, a transcriptional activator of c-myc.
  • p38 binding promotes FBP ubiquitination and degradation, downregulating c-myc.
  • TGF-beta induces p38 expression and nuclear translocation, regulating FBP and c-myc.

Conclusions:

  • p38 plays an essential role in lung alveolar type II cell differentiation via FBP/c-myc regulation.
  • p38 acts as a mediator of TGF-beta signaling during lung development.
  • Dysregulation of p38 function leads to severe developmental defects and neonatal lethality.

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