Abstract
Differential gene expression through alternative pre-mRNA splicing is crucial to various physiological and pathological conditions. Upon activation of B and T lymphocytes during an immune response, variant isoforms of the cell surface molecule CD44 are generated by alternative pre-mRNA splicing. We show here that in primary mouse T cells as well as in the murine LB-17 T-cell line upregulation of variant CD44 mRNA species upon T-cell activation requires activation of the MEK-ERK pathway. By employing mutant signaling molecules and a novel luciferase-based splice reporter system we demonstrate that the Ras-Raf-MEK-ERK signaling cascade, but not the p38 MAP-kinase pathway, activates a mechanism that retains variant CD44 exon v5 sequence in mature mRNA. The findings demonstrate that a highly conserved pleiotropic signaling pathway links extracellular cues to splice regulation, providing an avenue for tissue-specific, developmental or pathology-associated splicing decisions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing*
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Animals
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Cells, Cultured
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Exons
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Gene Expression Regulation
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Gene Silencing
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Genes, Reporter
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Hyaluronan Receptors / genetics*
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Hyaluronan Receptors / metabolism
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Luciferases / genetics
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP Kinase Signaling System*
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-raf / metabolism
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Proto-Oncogene Proteins p21(ras) / metabolism
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RNA Precursors*
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism
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Tumor Cells, Cultured
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Up-Regulation
Substances
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Hyaluronan Receptors
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Protein Isoforms
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RNA Precursors
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Luciferases
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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Proto-Oncogene Proteins p21(ras)