Emerging roles of RNA and RNA-binding protein network in cancer cells

  • Published : 2009.03.31


Recent advances in RNA biology reveal unexpected diversity and complexity of cellular RNA metabolism. RNA-binding proteins (RBPs) are essential players in RNA metabolism, regulating RNA splicing, transport, surveillance, decay and translation. Aberrant expression of RBPs affects many steps of RNA metabolism, significantly altering expression of RNA. Thus, altered expression and dysfuncting of RBPs are implicated in the development of various diseases including cancer. In this minireview, we briefly describe emerging roles of RBPs as a global coordinator of post-transcriptional steps and altered RBP as a global generator of cancer related RNA alternative splicing. Identification and characterization of the RNA-RBP network would expand the scope of cellular RNA metabolism and provide novel anti-cancer therapeutic targets based on cancer specific RNA-RBP interaction.


Alternative splicing;Cancer;RNA-binding protein (RBP);RNA metabolism


  1. Keene, J. D. (2007) RNA regulons: coordination of post-transcriptional events. Nat. Rev. Genet. 8, 533-543
  2. Birzele, F., Csaba, G. and Zimmer, R. (2008) Alternative splicing and protein structure evolution. Nucleic. Acids. Res. 36, 550-558
  3. House, A. E. and Lynch, K. W. (2008) Regulation of alternative splicing: more than just the ABCs. J. Biol. Chem. 283, 1217-1221
  4. Stamm, S. (2008) Regulation of alternative splicing by reversible protein phosphorylation. J. Biol. Chem. 283, 1223-1227
  5. Wang, G. S. and Cooper, T. A. (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat. Rev. Genet. 8, 749-761
  6. and Montuenga, L. M. (2007) Alternative splicing: an emerging topic in molecular and clinical oncology. Lacent. Onc. 8, 349-357
  7. Audic, Y. and Hartley, R. S. (2004) Post-transcriptional regulation in cancer. Biol. Cell 96, 479-498
  8. Naor, D., Nedvetzki, S., Golan, I., Melnik, L. and Faitelson, Y. (2002) CD44 in cancer. Crit. Rev. Clin. Lab. Sci. 39, 527-579
  9. Karni, R., Hippo, Y. Lowe, S. W. and Krainer, A. R. (2008) The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc. Natl. Acad. Sci. U. S. A. 105, 15323-15327
  10. Lukong, K. E. and Richard, S. (2003) Sam68, the KH domain- containing superSTAR. Biochim. Biophys. Acta. 1653, 73-86
  11. Lee, H. K., Kwak, H. Y., Hur, J., Kim, I. A., Yang, J. S., Park, M. W., Yu, J. and Jeong, S. (2007) $\beta$-catenin regulates multiple steps of RNA metabolism as revealed by RNA aptamer in colon cancer cells. Cancer Res. 67, 9315-9321
  12. Licatalosi, D. D., Mele, A., Fak, J. J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., Darnell, J. C. and Darnell, R. B. (2008) HITS-CLIP yields genome- wide insights into brain alternative RNA processing. Nature 456, 464-469
  13. Lee, H. K. and Jeong, S. (2006) $\beta$-catenin stabilizes cyclooxygenase- 2 mRNA by interacting with AU-rich elements of 3'-UTR. Nucleic. Acids. Res. 34, 5705-5714
  14. Li, H., Watford, W., Li, C., Parmelee, A., Bryant, M. A., Deng, C., O'Shea, J. and Lee, S. B. (2007) Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development. J. Clin. Incest. 117, 1314-1323
  15. Fedor, M. J. (2008) Alternative splicing minireview series: combinatorial control facilitates splicing regulation of gene expression and enhances genome diversity. J. Biol. Chem. 283, 1209-1210
  16. Kim, E., Goren, A. and Ast, G. (2008) Insights into the connection between cancer and alternative splicing. Trends Genet. 24, 7-10
  17. Riggi, N., Cironi, L., Suv$\grave{a}$, M. L. and Stamenkovic, I. (2007) Sarcomas:genetics, signaling, and cellular origins. Part 1: The fellowship of TET. J. Pathol. 213, 4-20
  18. Glisovic, T., Bachorik, J. L., Yong, J. and Dreyfuss, G. (2008) RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett. 582, 977-1986
  19. Lukong, K. E., Chang K. W., Khandjian, E. W. and Richard, S. (2008) RNA-binding proteins in human genetic disease. Trends Genet. 24, 416-425
  20. Kim, E. Goren, A. and Ast, G. Alternative splicing and disease. RNA Biol. 5, 1-3
  21. and Ilaria, R. L. Jr. (2005) Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells results in EWS/FLI-1-dependent, ewing sarcoma-like tumors. Cancer Res. 65, 8698-8705
  22. Maniatis, T. and Reed, R. (2002) An extensive network of coupling among gene expression machines. Nature 416, 499-506
  23. Stickeler, E., Kittrell, F., Medina, D. and Berget, S. M. (1999) Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene 18, 3574-3582
  24. Orend, G. and Chiquet-Ehrismann, R. (2006) Tenascin-C induced signaling in cancer. Cancer Lett. 8, 143-163
  25. Ferrara, N., Gerber, H. P. and LeCouter, J. (2003) The biology of VEGF and its receptors. Nat. Med. 9, 669-676
  26. Cooper, T. A., Wan, L. and Dreyfuss, D. (2009) RNA and disease. Cell 136, 777-793
  27. Bus$\grave{a}$, R., Paronetto, M. P., Farini, D., Pierantozzi, E., Botti, F., Angelini, D. F. and Attisani, F. (2007) The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells. Oncogene 26, 4372-4382
  28. and Krainer, A. R. (2007) The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14, 185-193
  29. Sharp, P. A. (2009) The centrality of RNA. Cell 136, 577- 580
  30. Moore, M. J. and Proudfoot, N. J. (2009) Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688-700
  31. Huang, Y. and Steitz, J. A. (2005) SRprises along a messenger's journey. Mol. Cell 17, 613-615
  32. Stamm, S., Ben-Ari, S., Rafalska, I., Tang, Y., Zhang, Z., Toiber, D., Thanaraj, T. A. and Soreq, H. (2005) Function of alternative splicing. Gene 344, 1-20
  33. Yin, Y., Chung, P., de Rooij, D. G., Akhmedov, A., Ashley, T. and Ron, D. (2000) Male sterility and enhanced radiation sensitivity in TLS (-/-) mice. EMBO J. 19, 453-462
  34. Lee, H. K., Choi, Y. S., Park, Y. A. and Jeong, S. (2006) Modulation of oncogenic transcription and alternative splicing by $\beta$-catenin and an RNA aptamer in colon cancer cells. Cancer Res. 66, 10560-10566
  35. Orphanides, G. and Reinberg, D. (2002) A unified theory of gene expression. Cell 108, 439-451
  36. Sanford, J. R., Coutinho, P., Hackett, J. A., Wang, X., Ranahan, W. and Caceres, J. F. (2008) Identification of nuclear and cytoplasmic mRNA targets for the shuttling protein SF2/ASF. PLoS ONE 3, e3369
  37. Matter, N., Herrlich, P. and K$\ddot{o}$nig, H. (2002) Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420, 691-695
  38. Grunstein, J., Masbad, J. J., Hickey, R., Giordano, F. and Johnson, R. S. (2000) Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature. Mol. Cell Biol. 20, 7282-7291
  39. Michlewski, G., Sanford, J. R. and Caceres, J. F. (2008) The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol. Cell 30, 179-189
  40. Lunde, B. M., Moore, C. and Varani, G. (2007) RNA-binding proteins: modular design for efficient function. Nat. Rev. Mol. Cell Biol. 8, 479-490
  41. Scholzov$\acute{a}$, E., Mal$\acute{i}$k, R., $\check{S}$ev$\check{c}$ik, J. and Kleibl, Z. (2007) RNA regulation and cancer development. Cancer Lett. 246, 12-23
  42. Jele, N. Ule, J., Zivin, M. and Darnell, R. B. (2007) Evolution of Nova-dependent splicing regulation in the brain. PLoS Genet. 3, e173
  43. Hertel, K. J. (2008) Combinatorial control of exon recognition. J. Biol. Chem. 283, 1211-1215
  44. Xu, Q. and Lee, C. (2003) Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic. Acids. Res. 31, 5635-5643
  45. Cech, T. R. (2009) Crawling out of RNA world. Cell 136, 599-602
  46. Sanford, J. R., Gray, N. K., Beckmann, K. and Caceres, J. F. (2004) A novel role for shuttling SR proteins in mRNA translation. Genes. Dev. 18, 755-768
  47. Ben-Dov, C., Hartmann, B., Lundgren, J. and Valcarcel, J. (2008) Genome-wide analysis of alternative pre-mRNA splicing. J. Biol. Chem. 283, 1229-1233
  48. Sonenberg, N. and Hinnebusch, A. G. (2007) New modes of translational control in development, behavior, and disease. Mol. Cell 28, 721-729
  49. Hogan, D. J., Riordan, D. P., Gerber, A. P., Herschlag, D. and Brown, P. O. (2008) Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system. PLoS Biol. 6, e255
  50. Sanford, J. R., Ellis, J. D., Cazalla, D. and Caceres, J. F. (2005) Reversible phosphorylation differentially affects nuclear and cytoplasmic functions of splicing factor 2/alter native splicing factor. Proc. Natl. Acad. Sci. U. S. A. 102, 15042-15047
  51. Gerber, A. P., Herschlag, D. and Brown, P. O. (2004) Extensive association of functionally and cytotopically related mRNAs with Puf family RNA-binding protein in yeast. PLoS Biol. 2, 342-354
  52. Torchia, E. C., Boyd, K., Rehg, J. E., Qu, C. and Baker, S. J. (2007) EWS/FLI-1 induces rapid onset of myeloid/erythroid leukemia in mice. Mol. Cell Biol. 27, 7918-7934
  53. Fleischer, T. C., Weaver, C. M., McAfee, K. J., Jennings, J. L. and Link, A. J. (2006) Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes Dev. 20, 1294-1307
  54. Venables, J. P. (2004) Aberrant and alternative splicing in cancer. Cancer Res. 64, 7647-7654

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