SRSF1-Regulated Alternative Splicing in Breast Cancer

Anczukow, O., Akerman, M., Clery, A., Wu, J., Shen, C., Shirole, N. H., Raimer, A., Sun, S., Jensen, M. A., Hua, Y., Allain, F. H., Krainer, A. R. (October 2015) SRSF1-Regulated Alternative Splicing in Breast Cancer. Mol Cell, 60 (1). pp. 105-17. ISSN 1097-4164 (Electronic)1097-2765 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26431027
DOI: 10.1016/j.molcel.2015.09.005

Abstract

Splicing factor SRSF1 is upregulated in human breast tumors, and its overexpression promotes transformation of mammary cells. Using RNA-seq, we identified SRSF1-regulated alternative splicing (AS) targets in organotypic three-dimensional MCF-10A cell cultures that mimic a context relevant to breast cancer. We identified and validated hundreds of endogenous SRSF1-regulated AS events. De novo discovery of the SRSF1 binding motif reconciled discrepancies in previous motif analyses. Using a Bayesian model, we determined positional effects of SRSF1 binding on cassette exons: binding close to the 5' splice site generally promoted exon inclusion, whereas binding near the 3' splice site promoted either exon skipping or inclusion. Finally, we identified SRSF1-regulated AS events deregulated in human tumors; overexpressing one such isoform, exon-9-included CASC4, increased acinar size and proliferation, and decreased apoptosis, partially recapitulating SRSF1's oncogenic effects. Thus, we uncovered SRSF1 positive and negative regulatory mechanisms, and oncogenic AS events that represent potential targets for therapeutics development.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL labs > Sordella lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 1 October 2015
Date Deposited: 06 Oct 2015 16:13
Last Modified: 05 Mar 2018 21:39
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31913

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