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

p38 is associated with a macromolecular tRNA synthetase complex. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality. Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory ...
distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc. Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.
Mesh Terms:
Amino Acyl-tRNA Synthetases, Animals, Animals, Newborn, Cell Differentiation, Cell Division, DNA Helicases, DNA-Binding Proteins, Down-Regulation, Gene Expression Regulation, Homozygote, Humans, Immunoenzyme Techniques, Lung Neoplasms, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Pulmonary Alveoli, Reverse Transcriptase Polymerase Chain Reaction, Saccharomyces cerevisiae, Signal Transduction, Transforming Growth Factor beta, Tumor Cells, Cultured, Two-Hybrid System Techniques, Ubiquitins, p38 Mitogen-Activated Protein Kinases
Nat. Genet.
Date: Jul. 01, 2003
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