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

• Published in: Nature structural & molecular biology Vol. 19; no. 2; pp. 220 - 228
• Main Authors: Anczuków, Olga, Rosenberg, Avi Z, Akerman, Martin, Das, Shipra, Zhan, Lixing, Karni, Rotem, Muthuswamy, Senthil K, Krainer, Adrian R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2012; Nature Publishing Group
• Subjects: 631/337/1645/1792; 631/80/82/23; 692/420/755; 692/699/67/1347; Animals; Apoptosis; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cells; Epithelial Cells - physiology; Gene expression; Genetic aspects; Humans; Life Sciences; Membrane Biology; Mice; Models, Biological; Nuclear Proteins - metabolism; Organ Culture Techniques; Physiological aspects; Protein Structure; RNA-Binding Proteins - metabolism; Serine-Arginine Splicing Factors; Transcription factors; Tumors; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2207

The splicing factor SRSF1 is an oncoprotein that is upregulated in human tumors, including breast cancer tumors. New
in vitro
and
in vivo
analyses reveal SRSF1's ability to transform human mammary epithelial cells and promote mammary gland tumorigenesis in a mouse model by regulating apoptosis and proliferation and cooperating with Myc while also uncovering potential downstream therapeutic targets.
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.