Splicing-Factor Oncoprotein SRSF1 Stabilizes p53 via RPL5 and Induces Cellular Senescence

• Published in: Molecular cell 2013-04, Vol.50 (1), p.56-66
• Main Authors: Fregoso, Oliver I., Das, Shipra, Akerman, Martin, Krainer, Adrian R.
• Format: Article
• Language: English
• Subjects: Cancer; cell cycle; Cell Cycle Checkpoints; Cell Proliferation; cell senescence; Cellular Senescence; fibroblasts; gene expression; HeLa Cells; Humans; neoplasms; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; oncogene proteins; physiology; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Stability; Proto-Oncogene Proteins c-mdm2 - metabolism; Ribosomal Proteins - metabolism; ribosomes; Ribosomes - enzymology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Serine-Arginine Splicing Factors; Signal Transduction; spliceosomes; Stress, Physiological; Transfection; tumor suppressor protein p53; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.02.001

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. [Display omitted] ► SRSF1 is a component of a ribosomal protein RPL5/MDM2 complex that stabilizes p53 ► Through this complex, SRSF1 is required for ribosomal-stress-mediated p53 activation ► Overexpression of SRSF1 in primary cells leads to oncogene-induced senescence ► SRSF1-induced senescence is mediated by the ribosomal-stress response and p53