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Mol Cell. 2015 Oct 1;60(1):105-17. doi: 10.1016/j.molcel.2015.09.005.

SRSF1-Regulated Alternative Splicing in Breast Cancer.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Institute for Molecular Biology and Biophysics, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY 11794, USA.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY 11794, USA.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: krainer@cshl.edu.

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.

PMID:
26431027
PMCID:
PMC4597910
DOI:
10.1016/j.molcel.2015.09.005
[Indexed for MEDLINE]
Free PMC Article
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