Regulation of CD44 Alternative Splicing by SRm160 and Its Potential Role in Tumor Cell Invasion

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2005 Dec 16

PMID 16354706

Citations 109

Authors

Chonghui Cheng

Phillip A Sharp

Affiliations

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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.

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References

Choi S, Takahashi K, Eto H, Yoon S, Tanabe K . CD44s expression in human colon carcinomas influences growth of liver metastases. Int J Cancer. 2000; 85(4):523-6. DOI: 10.1002/(sici)1097-0215(20000215)85:4<523::aid-ijc13>3.0.co;2-6. View

Blencowe B, Issner R, Nickerson J, Sharp P . A coactivator of pre-mRNA splicing. Genes Dev. 1998; 12(7):996-1009. PMC: 316672. DOI: 10.1101/gad.12.7.996. View

Morrison H, SHERMAN L, Legg J, Banine F, Isacke C, Haipek C . The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 2001; 15(8):968-80. PMC: 312675. DOI: 10.1101/gad.189601. View

Weg-Remers S, Ponta H, Herrlich P, Konig H . Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J. 2001; 20(15):4194-203. PMC: 149173. DOI: 10.1093/emboj/20.15.4194. View

Pereira P, Rubenthiran U, Kaneko M, Jothy S, Smith A . CD44s expression mitigates the phenotype of human colorectal cancer hepatic metastases. Anticancer Res. 2001; 21(4A):2713-7. View

Sherman L, Wainwright D, Ponta H, Herrlich P . A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth. Genes Dev. 1998; 12(7):1058-71. PMC: 316674. DOI: 10.1101/gad.12.7.1058. View

Tacke R, Tohyama M, Ogawa S, Manley J . Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing. Cell. 1998; 93(1):139-48. DOI: 10.1016/s0092-8674(00)81153-8. View

Konig H, Ponta H, Herrlich P . Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator. EMBO J. 1998; 17(10):2904-13. PMC: 1170631. DOI: 10.1093/emboj/17.10.2904. View

Sleeman J, Rahmsdorf U, Steffen A, Ponta H, Herrlich P . CD44 variant exon v5 encodes a tyrosine that is sulphated. Eur J Biochem. 1998; 255(1):74-80. DOI: 10.1046/j.1432-1327.1998.2550074.x. View

10.

Katagiri Y, Sleeman J, Fujii H, Herrlich P, Hotta H, Tanaka K . CD44 variants but not CD44s cooperate with beta1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis. Cancer Res. 1999; 59(1):219-26. View

11.

van der Voort R, Taher T, Wielenga V, Spaargaren M, Prevo R, Smit L . Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter factor-induced signal transduction through the receptor tyrosine kinase c-Met. J Biol Chem. 1999; 274(10):6499-506. DOI: 10.1074/jbc.274.10.6499. View

12.

Eldridge A, Li Y, Sharp P, Blencowe B . The SRm160/300 splicing coactivator is required for exon-enhancer function. Proc Natl Acad Sci U S A. 1999; 96(11):6125-30. PMC: 26846. DOI: 10.1073/pnas.96.11.6125. View

13.

Wu S, Sun G, Hsieh D, Chen A, Chen H, Chang S . Correlation of CD44v5 expression with invasiveness and prognosis in renal cell carcinoma. J Formos Med Assoc. 2003; 102(4):229-33. View

14.

Lee S, Harn H, Lin T, Yeh K, Liu Y, Tsai C . Prognostic significance of CD44v5 expression in human thymic epithelial neoplasms. Ann Thorac Surg. 2003; 76(1):213-8; discussion 218. DOI: 10.1016/s0003-4975(03)00319-9. View

15.

Zhu J, Shendure J, Mitra R, Church G . Single molecule profiling of alternative pre-mRNA splicing. Science. 2003; 301(5634):836-8. DOI: 10.1126/science.1085792. View

16.

Black D . Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem. 2003; 72:291-336. DOI: 10.1146/annurev.biochem.72.121801.161720. View

17.

McCracken S, Longman D, Johnstone I, Caceres J, Blencowe B . An evolutionarily conserved role for SRm160 in 3'-end processing that functions independently of exon junction complex formation. J Biol Chem. 2003; 278(45):44153-60. DOI: 10.1074/jbc.M306856200. View

18.

Babic I, Jakymiw A, Fujita D . The RNA binding protein Sam68 is acetylated in tumor cell lines, and its acetylation correlates with enhanced RNA binding activity. Oncogene. 2004; 23(21):3781-9. DOI: 10.1038/sj.onc.1207484. View

19.

McLaren M, Asai K, Cochrane A . A novel function for Sam68: enhancement of HIV-1 RNA 3' end processing. RNA. 2004; 10(7):1119-29. PMC: 1370602. DOI: 10.1261/rna.5263904. View

20.

Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I . A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991; 65(1):13-24. DOI: 10.1016/0092-8674(91)90403-l. View