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.
Kim
Min Jung
MJ
National Creative Research Initiatives Center for ARS Network, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Park
Bum-Joon
BJ
Kang
Young-Sun
YS
Kim
Hyoung June
HJ
Park
Jae-Hyun
JH
Kang
Jung Woo
JW
Lee
Sang Won
SW
Han
Jung Min
JM
Lee
Han-Woong
HW
Kim
Sunghoon
S
D000604:Amino Acyl-tRNA Synthetases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002455:Cell Division; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D014452:Ubiquitins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; C118921:Fubp protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D016212:Transforming Growth Factor beta; D014452:Ubiquitins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004265:DNA Helicases; D000604:Amino Acyl-tRNA Synthetases