Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway.
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.
Weg-Remers
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Forschungszentrum Karlsruhe der Helmholtz-Gemeinschaft, Institut für Toxikologie und Genetik, Karlsruhe, Germany. susanne.weg@itg.fzk.de
Ponta
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Herrlich
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König
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D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D005091:Exons; D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012322:RNA Precursors; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012322:RNA Precursors; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)