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Molecular and Cellular Biology, January 2006, p. 362-370, Vol. 26, No. 1
0270-7306/06/$08.00+0 doi:10.1128/MCB.26.1.362-370.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Regulation of CD44 Alternative Splicing by SRm160 and Its Potential Role in Tumor Cell Invasion
Chonghui Cheng1 and
Phillip A. Sharp1,2*
Center for Cancer Research,1
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 021392
Received 28 June 2005/
Returned for modification 11 August 2005/
Accepted 8 October 2005
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.
* Corresponding author. Mailing address: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139-4307. Phone: (617) 253-6421. Fax: (617) 253-3867. E-mail: sharppa{at}mit.edu.
Molecular and Cellular Biology, January 2006, p. 362-370, Vol. 26, No. 1
0022-538X/06/$08.00+0 doi:10.1128/MCB.26.1.362-370.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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Copyright © 2006 by the American Society for Microbiology. All rights reserved.