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

Fregoso, O. I., Das, S., Akerman, M., Krainer, A. R. (March 2013) Splicing-Factor Oncoprotein SRSF1 Stabilizes p53 via RPL5 and Induces Cellular Senescence. Molecular Cell, 50 (1). pp. 56-66. ISSN 1097-2765

URL: http://www.ncbi.nlm.nih.gov/pubmed/23478443

DOI: 10.1016/j.molcel.2013.02.001

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.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:	Akerman, Martin Das, Shipra Fregoso, Oliver I. Krainer, Adrian R.
Communities:	CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL Cancer Center Shared Resources > Antibody and Phage Display Service CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL Cancer Center Shared Resources > Proteomics Service CSHL Post Doctoral Fellows CSHL labs > Krainer lab School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > Mass Spectrometry Service
Depositing User:	Matt Covey
Date:	7 March 2013
Date Deposited:	29 Mar 2013 19:12
Last Modified:	30 Oct 2015 14:31
PMCID:	PMC3628402
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/28070

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