Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic signaling pathways.
Regulation of alternative pre-mRNA splicing, recognized as increasingly important in causing human disease, was studied using the CD44 gene, whose splice variants have been implicated in tumor progression. We identified heterogeneous ribonucleoprotein (hnRNP) A1 as a protein interacting in vitro and in vivo with regulatory splice elements in CD44 variant exon v5. Transient overexpression of hnRNP A1 prevented v5 exon inclusion, dependent on the exonic elements. HnRNP A1-dependent repression was exon-specific and could be relieved by coexpression of oncogenic forms of Ras and Cdc42. The results define hnRNP A1 as a decisive part of an oncogene-regulated splice-silencing complex, which can select between multiple alternatively spliced exons.
Matter
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N
Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, and Universität Karlsruhe, Institut für Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
Marx
M
M
Weg-Remers
S
S
Ponta
H
H
Herrlich
P
P
König
H
H
D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation; D000939:Epitopes; D005091:Exons; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016296:Mutagenesis; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins
D000939:Epitopes; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D012313:RNA; D015689:Oncogene Protein p21(ras); D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins