title: Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion.
abstract: The multiple isoforms of the transmembrane glycoprotein CD44 are produced by alternative RNA splicing. Expression of CD44 isoforms containing variable 5 exon (v5) correlates with enhanced malignancy and invasiveness of some tumors. Here we demonstrate that SRm160, a splicing coactivator, regulates CD44 alternative splicing in a Ras-dependent manner. Overexpression of SRm160 stimulates inclusion of CD44 v5 when Ras is activated. Conversely, small interfering RNA (siRNA)-mediated silencing of SRm160 significantly reduces v5 inclusion. Immunoprecipitation shows association of SRm160 with Sam68, a protein that also stimulates v5 inclusion in a Ras-dependent manner, suggesting that these two proteins interact to regulate CD44 splicing. Importantly, siRNA-mediated depletion of CD44 v5 decreases tumor cell invasion. Reduction of SRm160 by siRNA transfection downregulates the endogenous levels of CD44 isoforms, including v5, and correlates with a decrease in tumor cell invasiveness.
authors.affiliation: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.
authors.forename: Chonghui
authors.initials: C
authors.lastname: Cheng
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Sharp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; C489559:KHDRBS1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C111710:SRRM1 protein, human; D018631:ras Proteins