title: RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation.
abstract: Alternative splicing regulators have emerged as new players in cancer development, modulating the activities of many tumor suppressors and oncogenes and regulating the signaling pathways. However, little is known about the mechanisms by which these oncogenic splicing factors lead to cellular transformation. We have shown previously that the splicing factor serine and arginine splicing factor 1 (SRSF1; SF2/ASF) is a proto-oncogene, which is amplified in breast cancer and transforms immortal cells when overexpressed. In this study, we performed a structure-function analysis of SRSF1 and found that the RNA recognition motif 1 (RRM1) domain is required for its oncogenic activity. Deletion of RRM1 eliminated the splicing activity of SRSF1 on some of its endogenous targets. Moreover, we found that SRSF1 elevates the expression of B-Raf and activates the mitogen-activated protein kinase kinase (MEK) extracellular signal-regulated kinase (ERK) pathway and that RRM1 is required for this activation as well. B-Raf-MEK-ERK activation by SRSF1 contributes to transformation as pharmacological inhibition of MEK1 inhibits SRSF1-mediated transformation. In conclusion, RRM1 of SRSF1 is both required (and when tethered to the RS domain) also sufficient to activate the Raf-MEK-ERK pathway and to promote cellular transformation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem 91120, Israel and.
authors.forename: Ariel
authors.initials: A
authors.lastname: Shimoni-Sebag
authors.forename: Ilana
authors.initials: I
authors.lastname: Lebenthal-Loinger
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D000090063:Proto-Oncogene Mas; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000502:physiology*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000068103:Serine-Arginine Splicing Factors; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; C498690:Rrm1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases