The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation

Anczukow, O., Rosenberg, A. Z., Akerman, M., Das, S., Zhan, L., Karni, R., Muthuswamy, S. K., Krainer, A. R. (January 2012) The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nature Structural Molecular Biology, 19 (2). pp. 220-228. ISSN 1545-9985 (Electronic)1545-9985 (Linking)

Abstract

The splicing-factor oncoprotein SRSF1 (also known as SF2/ASF or ASF/SF2) is upregulated in breast cancers. We investigated the ability of SRSF1 to transform human and mouse mammary epithelial cells in vivo and in vitro. SRSF1-overexpressing COMMA-1D cells formed tumors, following orthotopic transplantation to reconstitute the mammary gland. In three-dimensional (3D) culture, SRSF1-overexpressing MCF-10A cells formed larger acini than control cells, reflecting increased proliferation and delayed apoptosis during acinar morphogenesis. These effects required the first RNA-recognition motif and nuclear functions of SRSF1. SRSF1 overexpression promoted alternative splicing of BIM (also known as BCL2L11) and BIN1 to produce isoforms that lack pro-apoptotic functions and contribute to the phenotype. Finally, SRSF1 cooperated specifically with MYC to transform mammary epithelial cells, in part by potentiating eIF4E activation, and these cooperating oncogenes are significantly coexpressed in human breast tumors. Thus, SRSF1 can promote breast cancer, and SRSF1 itself or its downstream effectors may be valuable targets for the development of therapeutics.

Item Type:	Paper
Additional Information:
Subjects:	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 > apoptosis organs, tissues, organelles, cell types and functions > organs types and functions > breast organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:	Akerman, Martin Anczukow, Olga Das, Shipra Karni, Rotem Krainer, Adrian R. Muthuswamy, Senthil K. Rosenberg, Avi Zhan, Lixing
Communities:	CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Shared Resources > Animal Services 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 Post Doctoral Fellows CSHL labs > Krainer lab CSHL labs > Muthuswamy lab CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User:	Matt Covey
Date:	15 January 2012
Date Deposited:	31 Jan 2013 21:49
Last Modified:	16 Oct 2015 19:33
PMCID:	PMC3272117
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/26890

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