Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Extracellular Signal-Regulated MAP Kinases / physiology*
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GATA3 Transcription Factor
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Histones / metabolism
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MAP Kinase Signaling System / physiology*
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Mice
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Mice, Inbred C57BL
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Nuclear Proteins / physiology
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Proteasome Endopeptidase Complex / physiology*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-mdm2
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Th2 Cells / cytology*
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Trans-Activators / metabolism*
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Ubiquitin / metabolism*
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Zinc Fingers
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ras Proteins / physiology*
Substances
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Histones
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Nuclear Proteins
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Proto-Oncogene Proteins
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Trans-Activators
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Ubiquitin
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Extracellular Signal-Regulated MAP Kinases
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Proteasome Endopeptidase Complex
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ras Proteins