Ras-ERK MAPK cascade regulates GATA3 stability and Th2 differentiation through ubiquitin-proteasome pathway.
Differentiation of naive CD4 T cells into Th2 cells requires protein expression of GATA3. Interleukin-4 induces STAT6 activation and subsequent GATA3 transcription. Little is known, however, on how T cell receptor-mediated signaling regulates GATA3 and Th2 cell differentiation. Here we demonstrated that T cell receptor-mediated activation of the Ras-ERK MAPK ... cascade stabilizes GATA3 protein in developing Th2 cells through the inhibition of the ubiquitin-proteasome pathway. Mdm2 was associated with GATA3 and induced ubiquitination on GATA3, suggesting its role as a ubiquitin-protein isopeptide ligase for GATA3 ubiquitination. Thus, the Ras-ERK MAPK cascade controls GATA3 protein stability by a post-transcriptional mechanism and facilitates GATA3-mediated chromatin remodeling at Th2 cytokine gene loci leading to successful Th2 cell differentiation.
Mesh Terms:
Acetylation, Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Extracellular Signal-Regulated MAP Kinases, GATA3 Transcription Factor, Histones, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Nuclear Proteins, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Th2 Cells, Trans-Activators, Ubiquitin, Zinc Fingers, ras Proteins
Acetylation, Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Extracellular Signal-Regulated MAP Kinases, GATA3 Transcription Factor, Histones, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Nuclear Proteins, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Th2 Cells, Trans-Activators, Ubiquitin, Zinc Fingers, ras Proteins
J. Biol. Chem.
Date: Aug. 19, 2005
PubMed ID: 15975924
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