title: Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence.
abstract: Splicing and translation are highly regulated steps of gene expression. Altered expression of proteins involved in these processes can be deleterious. Therefore, the cell has many safeguards against such misregulation. We report that the oncogenic splicing factor SRSF1, which is overexpressed in many cancers, stabilizes the tumor suppressor protein p53 by abrogating its MDM2-dependent proteasomal degradation. We show that SRSF1 is a necessary component of an MDM2/ribosomal protein complex, separate from the ribosome, that functions in a p53-dependent ribosomal-stress checkpoint pathway. Consistent with the stabilization of p53, increased SRSF1 expression in primary human fibroblasts decreases cellular proliferation and ultimately triggers oncogene-induced senescence (OIS). These findings underscore the deleterious outcome of SRSF1 overexpression and identify a cellular defense mechanism against its aberrant function. Furthermore, they implicate the RPL5-MDM2 complex in OIS and demonstrate a link between spliceosomal and ribosomal components, functioning independently of their canonical roles, to monitor cellular physiology and cell-cycle progression.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Oliver I
authors.initials: OI
authors.lastname: Fregoso
authors.forename: Shipra
authors.initials: S
authors.lastname: Das
authors.forename: Martin
authors.initials: M
authors.lastname: Akerman
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D016922:Cellular Senescence; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012262:Ribonucleoside Diphosphate Reductase; D012269:Ribosomal Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000201:enzymology*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction; D013312:Stress, Physiological; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C549166:ribosomal protein L5, human; D000068103:Serine-Arginine Splicing Factors; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex