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

Nature Genetics volume 34, pages 330–336 (2003)Cite this article

Abstract

p38 is associated with a macromolecular tRNA synthetase complex1. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality2. 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-myc3. 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-β (TGF-β) 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-β signaling and its functional importance in the control of c-myc during lung differentiation.

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Figure 1: Protein synthesis, cell growth and histological characteristics of p38-deficient mice.
Figure 2: Defect in the differentiation of alveolar type II cells and surfactant production in lungs of p38-deficient mice.
Figure 3: Interaction of p38 with FBP.
Figure 4: p38-dependent ubiquitination and degradation of FBP.
Figure 5: The effect of p38 on cell proliferation and differentiation and its role in the TGF-β signaling pathway.
Figure 6: TGF-β induced nuclear translocation of p38.

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Acknowledgements

This work was supported by a grant of National Creative Research Initiatives from Ministry of Science and Technology, Korea.

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Authors and Affiliations

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

    Min Jung Kim, Bum-Joon Park, Young-Sun Kang, Hyoung June Kim, Jae-Hyun Park, Jung Woo Kang, Sang Won Lee & Sunghoon Kim

  2. Imagene, Biotechnology Incubation Center, Seoul National University, Seoul, 151-742, Korea

    Jung Min Han

  3. Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, 440-746, Korea

    Han-Woong Lee

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Kim, M., Park, BJ., Kang, YS. et al. Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. Nat Genet 34, 330–336 (2003). https://doi.org/10.1038/ng1182

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