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BioMed Research International
Volume 2015, Article ID 543067, 13 pages
http://dx.doi.org/10.1155/2015/543067
Review Article

Splicing Regulation: A Molecular Device to Enhance Cancer Cell Adaptation

1Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy
2Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy

Received 30 January 2015; Accepted 23 March 2015

Academic Editor: Peter Jordan

Copyright © 2015 Vittoria Pagliarini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. I. B. Rogozin, L. Carmel, M. Csuros, and E. V. Koonin, “Origin and evolution of spliceosomal introns,” Biology Direct, vol. 7, article 11, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. M. J. Moore and N. J. Proudfoot, “Pre-mRNA processing reaches back to transcription and ahead to translation,” Cell, vol. 136, no. 4, pp. 688–700, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. C. L. Will and R. Lührmann, “Spliceosome structure and function,” Cold Spring Harbor Perspectives in Biology, vol. 3, no. 7, pp. 1–2, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. A. A. Patel and J. A. Steitz, “Splicing double: insights from the second spliceosome,” Nature Reviews Molecular Cell Biology, vol. 4, no. 12, pp. 960–970, 2003. View at Publisher · View at Google Scholar · View at Scopus
  5. A. G. Matera and Z. Wang, “A day in the life of the spliceosome,” Nature Reviews Molecular Cell Biology, vol. 15, no. 2, pp. 108–121, 2014. View at Publisher · View at Google Scholar · View at Scopus
  6. D. L. Black, “Mechanisms of alternative pre-messenger RNA splicing,” Annual Review of Biochemistry, vol. 72, pp. 291–336, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Busch and K. J. Hertel, “Evolution of SR protein and hnRNP splicing regulatory factors,” Wiley Interdisciplinary Reviews: RNA, vol. 3, no. 1, pp. 1–12, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. S. Schwartz and G. Ast, “Chromatin density and splicing destiny: on the cross-talk between chromatin structure and splicing,” EMBO Journal, vol. 29, no. 10, pp. 1629–1636, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Pandya-Jones and D. L. Black, “Co-transcriptional splicing of constitutive and alternative exons,” RNA, vol. 15, no. 10, pp. 1896–1908, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. R. F. Luco, M. Allo, I. E. Schor, A. R. Kornblihtt, and T. Misteli, “Epigenetics in alternative pre-mRNA splicing,” Cell, vol. 144, no. 1, pp. 16–26, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. S. F. de Almeida and M. Carmo-Fonseca, “Reciprocal regulatory links between cotranscriptional splicing and chromatin,” Seminars in Cell & Developmental Biology, vol. 32, pp. 2–10, 2014. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Chen and J. L. Manley, “Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches,” Nature Reviews Molecular Cell Biology, vol. 10, no. 11, pp. 741–754, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. Q. Pan, O. Shai, L. J. Lee, B. J. Frey, and B. J. Blencowe, “Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing,” Nature Genetics, vol. 40, no. 12, pp. 1413–1415, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Sultan, M. H. Schulz, H. Richard et al., “A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome,” Science, vol. 321, no. 5891, pp. 956–960, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Merkin, C. Russell, P. Chen, and C. B. Burge, “Evolutionary dynamics of gene and isoform regulation in Mammalian tissues,” Science, vol. 338, no. 6114, pp. 1593–1599, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. N. L. Barbosa-Morais, M. Irimia, Q. Pan et al., “The evolutionary landscape of alternative splicing in vertebrate species,” Science, vol. 338, no. 6114, pp. 1587–1593, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. F. Heyd and K. W. Lynch, “Degrade, move, regroup: signaling control of splicing proteins,” Trends in Biochemical Sciences, vol. 36, no. 8, pp. 397–404, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. A. Kalsotra and T. A. Cooper, “Functional consequences of developmentally regulated alternative splicing,” Nature Reviews Genetics, vol. 12, no. 10, pp. 715–729, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. T. A. Cooper, L. Wan, and G. Dreyfuss, “RNA and disease,” Cell, vol. 136, no. 4, pp. 777–793, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. R. K. Singh and T. A. Cooper, “Pre-mRNA splicing in disease and therapeutics,” Trends in Molecular Medicine, vol. 18, no. 8, pp. 472–482, 2012. View at Publisher · View at Google Scholar · View at Scopus
  21. H. Feng, Z. Qin, and X. Zhang, “Opportunities and methods for studying alternative splicing in cancer with RNA-Seq,” Cancer Letters, vol. 340, no. 2, pp. 179–191, 2013. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Eswaran, A. Horvath, S. Godbole et al., “RNA sequencing of cancer reveals novel splicing alterations,” Scientific Reports, vol. 3, article 1689, 2013. View at Publisher · View at Google Scholar · View at Scopus
  23. C. J. David and J. L. Manley, “Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged,” Genes & Development, vol. 24, no. 21, pp. 2343–2364, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Zhang and J. L. Manley, “Misregulation of pre-mRNA alternative splicing in cancer,” Cancer Discovery, vol. 3, no. 11, pp. 1228–1237, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. G. Biamonti, M. Catillo, D. Pignataro, A. Montecucco, and C. Ghigna, “The alternative splicing side of cancer,” Seminars in Cell & Developmental Biology, vol. 32, pp. 30–36, 2014. View at Google Scholar
  26. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. C. M. Misquitta-Ali, E. Cheng, D. O'Hanlon et al., “Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer,” Molecular and Cellular Biology, vol. 31, no. 1, pp. 138–150, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. J. P. Venables, R. Klinck, A. Bramard et al., “Identification of alternative splicing markers for breast cancer,” Cancer Research, vol. 68, no. 22, pp. 9525–9531, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. A. Shilo, V. B. Hur, P. Denichenko et al., “Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development,” RNA, vol. 20, no. 4, pp. 505–515, 2014. View at Publisher · View at Google Scholar · View at Scopus
  30. P. I. Poulikakos, Y. Persaud, M. Janakiraman et al., “RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E),” Nature, vol. 480, no. 7377, pp. 387–390, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Wang, M. Zhou, B. Shi et al., “Identification of an exon 4-deletion variant of epidermal growth factor receptor with increased metastasis-promoting capacity,” Neoplasia, vol. 13, no. 5, pp. 461–471, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. Z. Zhou, J. Qiu, W. Liu et al., “The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus,” Molecular Cell, vol. 47, no. 3, pp. 422–433, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. J.-H. Ding, X.-Y. Zhong, J. C. Hagopian et al., “Regulated cellular partitioning of SR protein-specific kinases in mammalian cells,” Molecular Biology of the Cell, vol. 17, no. 2, pp. 876–885, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. S.-W. Jang, X. Liu, H. Fu et al., “Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons,” The Journal of Biological Chemistry, vol. 284, no. 36, pp. 24512–24525, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. C. Cheng, M. B. Yaffe, and P. A. Sharp, “A positive feedback loop couples Ras activation and CD44 alternative splicing,” Genes and Development, vol. 20, no. 13, pp. 1715–1720, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Ponta, L. Sherman, and P. A. Herrlich, “CD44: from adhesion molecules to signalling regulators,” Nature Reviews Molecular Cell Biology, vol. 4, no. 1, pp. 33–45, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Cheng and P. A. Sharp, “Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion,” Molecular and Cellular Biology, vol. 26, no. 1, pp. 362–370, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Matter, P. Herrlich, and H. König, “Signal-dependent regulation of splicing via phosphorylation of Sam68,” Nature, vol. 420, no. 6916, pp. 691–695, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. K. E. Knudsen, “The cyclin D1b splice variant: an old oncogene learns new tricks,” Cell Division, vol. 1, article 15, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. K. E. Knudsen, J. Alan Diehl, C. A. Haiman, and E. S. Knudsen, “Cyclin D1: polymorphism, aberrant splicing and cancer risk,” Oncogene, vol. 25, no. 11, pp. 1620–1628, 2006. View at Publisher · View at Google Scholar · View at Scopus
  41. C. J. Burd, C. E. Petre, L. M. Morey et al., “Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 7, pp. 2190–2195, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. P. Bielli, R. Busà, M. P. Paronetto, and C. Sette, “The RNA-binding protein Sam68 is a multifunctional player in human cancer,” Endocrine-Related Cancer, vol. 18, no. 4, pp. R91–R102, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Das and A. R. Krainer, “Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer,” Molecular Cancer Research, vol. 12, no. 9, pp. 1195–1204, 2014. View at Publisher · View at Google Scholar
  44. N. A. Olshavsky, C. E. S. Comstock, M. J. Schiewer et al., “Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene,” Cancer Research, vol. 70, no. 10, pp. 3975–3984, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. M. P. Paronetto, M. Cappellari, R. Busà et al., “Alternative splicing of the cyclin D1 proto-oncogene is regulated by the RNA-binding protein Sam68,” Cancer Research, vol. 70, no. 1, pp. 229–239, 2010. View at Publisher · View at Google Scholar
  46. H. Gerhardt, “VEGF and endothelial guidance in angiogenic sprouting,” Organogenesis, vol. 4, no. 4, pp. 241–246, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. P. M. Biselli-Chicote, A. R. C. P. Oliveira, E. C. Pavarino, and E. M. Goloni-Bertollo, “VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in cancer,” Journal of Cancer Research and Clinical Oncology, vol. 138, no. 3, pp. 363–370, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. K. A. Houck, N. Ferrara, J. Winer, G. Cachianes, B. Li, and D. W. Leung, “The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA,” Molecular Endocrinology, vol. 5, no. 12, pp. 1806–1814, 1991. View at Publisher · View at Google Scholar · View at Scopus
  49. D. G. Nowak, J. Woolard, E. M. Amin et al., “Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors,” Journal of Cell Science, vol. 121, no. 20, pp. 3487–3495, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Mavrou, K. Brakspear, M. Hamdollah-Zadeh et al., “Serine–arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer,” Oncogene, 2014. View at Publisher · View at Google Scholar
  51. D. G. Nowak, E. M. Amin, E. S. Rennel et al., “Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis,” The Journal of Biological Chemistry, vol. 285, no. 8, pp. 5532–5540, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. E. M. Amin, S. Oltean, J. Hua et al., “WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing,” Cancer Cell, vol. 20, no. 6, pp. 768–780, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. M. A. H. Zadeh, E. M. Amin, C. Hoareau-Aveilla et al., “Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance,” Molecular Oncology, vol. 9, no. 1, pp. 167–178, 2015. View at Publisher · View at Google Scholar
  54. S. Eswarappa, A. Potdar, W. Koch et al., “Programmed translational readthrough generates antiangiogenic VEGF-Ax,” Cell, vol. 157, no. 7, pp. 1605–1618, 2014. View at Publisher · View at Google Scholar
  55. M. Salton, T. C. Voss, and T. Misteli, “Identification by high-throughput imaging of the histone methyltransferase EHMT2 as an epigenetic regulator of VEGFA alternative splicing,” Nucleic Acids Research, vol. 42, no. 22, pp. 13662–13673, 2014. View at Publisher · View at Google Scholar
  56. S. Valastyan and R. A. Weinberg, “Tumor metastasis: molecular insights and evolving paradigms,” Cell, vol. 147, no. 2, pp. 275–292, 2011. View at Publisher · View at Google Scholar · View at Scopus
  57. B. de Craene and G. Berx, “Regulatory networks defining EMT during cancer initiation and progression,” Nature Reviews Cancer, vol. 13, no. 2, pp. 97–110, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. I. M. Shapiro, A. W. Cheng, N. C. Flytzanis et al., “An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype,” PLoS Genetics, vol. 7, no. 8, Article ID e1002218, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. C. C. Warzecha and R. P. Carstens, “Complex changes in alternative pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT),” Seminars in Cancer Biology, vol. 22, no. 5-6, pp. 417–427, 2012. View at Publisher · View at Google Scholar · View at Scopus
  60. R. L. Brown, L. M. Reinke, M. S. Damerow et al., “CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression,” Journal of Clinical Investigation, vol. 121, no. 3, pp. 1064–1074, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. F. di Modugno, P. Iapicca, A. Boudreau et al., “Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 47, pp. 19280–19285, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. K. Horiguchi, K. Sakamoto, D. Koinuma et al., “TGF-beta drives epithelial-mesenchymal transition through deltaEF1-mediated downregulation of ESRP,” Oncogene, vol. 31, no. 26, pp. 3190–3201, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. L. M. Reinke, Y. Xu, and C. Cheng, “Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition,” Journal of Biological Chemistry, vol. 287, no. 43, pp. 36435–36442, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. C. C. Warzecha, P. Jiang, K. Amirikian et al., “An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition,” The EMBO Journal, vol. 29, no. 19, pp. 3286–3300, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. F. Pelisch, D. Khauv, G. Risso et al., “Involvement of hnRNP A1 in the matrix metalloprotease-3-dependent regulation of Rac1 pre-mRNA splicing,” Journal of Cellular Biochemistry, vol. 113, no. 7, pp. 2319–2329, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. D. C. Radisky, D. D. Levy, L. E. Littlepage et al., “Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability,” Nature, vol. 436, no. 7047, pp. 123–127, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. V. Goncalves, A. Henriques, J. Pereira et al., “Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells,” RNA, vol. 20, no. 4, pp. 474–482, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Ghigna, S. Giordano, H. Shen et al., “Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene,” Molecular Cell, vol. 20, no. 6, pp. 881–890, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Collesi, M. M. Santoro, G. Gaudino, and P. M. Comoglio, “A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype,” Molecular and Cellular Biology, vol. 16, no. 10, pp. 5518–5526, 1996. View at Google Scholar · View at Scopus
  70. C. Valacca, S. Bonomi, E. Buratti et al., “Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene,” Journal of Cell Biology, vol. 191, no. 1, pp. 87–99, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. I. Cascino, G. Fiucci, G. Papoff, and G. Ruberti, “Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing,” The Journal of Immunology, vol. 154, no. 6, pp. 2706–2713, 1995. View at Google Scholar · View at Scopus
  72. J. Cheng, T. Zhou, C. Liu et al., “Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule,” Science, vol. 263, no. 5154, pp. 1759–1762, 1994. View at Publisher · View at Google Scholar · View at Scopus
  73. J. M. Izquierdo, N. Majós, S. Bonnal et al., “Regulation of fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition,” Molecular Cell, vol. 19, no. 4, pp. 475–484, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. M. P. Paronetto, I. Bernardis, E. Volpe et al., “Regulation of FAS exon definition and apoptosis by the Ewing sarcoma protein,” Cell Reports, vol. 7, no. 4, pp. 1211–1226, 2014. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Bonnal, C. Martínez, P. Förch, A. Bachi, M. Wilm, and J. Valcárcel, “RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition,” Molecular Cell, vol. 32, no. 1, pp. 81–95, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. J. M. Izquierdo, “Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition,” The Journal of Biological Chemistry, vol. 283, no. 27, pp. 19077–19084, 2008. View at Publisher · View at Google Scholar · View at Scopus
  77. J. M. Izquierdo, “Heterogeneous ribonucleoprotein C displays a repressor activity mediated by T-cell intracellular antigen-1-related/like protein to modulate Fas exon 6 splicing through a mechanism involving Hu antigen R,” Nucleic Acids Research, vol. 38, no. 22, pp. 8001–8014, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. D.-W. Seol and T. R. Billiar, “A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis,” Journal of Biological Chemistry, vol. 274, no. 4, pp. 2072–2076, 1999. View at Publisher · View at Google Scholar · View at Scopus
  79. S. M. Srinivasula, M. Ahmad, Y. Guo et al., “Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis,” Cancer Research, vol. 59, no. 5, pp. 999–1002, 1999. View at Google Scholar · View at Scopus
  80. J. C. Shultz, R. W. Goehe, D. S. Wijesinghe et al., “Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a,” Cancer Research, vol. 70, no. 22, pp. 9185–9196, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. R. W. Goehe, J. C. Shultz, C. Murudkar et al., “hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing,” The Journal of Clinical Investigation, vol. 120, no. 11, pp. 3923–3939, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. L. H. Boise, M. González-García, C. E. Postema et al., “bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death,” Cell, vol. 74, no. 4, pp. 597–608, 1993. View at Publisher · View at Google Scholar · View at Scopus
  83. D. Garneau, T. Revil, J.-F. Fisette, and B. Chabot, “Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x,” The Journal of Biological Chemistry, vol. 280, no. 24, pp. 22641–22650, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. P. Bielli, M. Bordi, V. D. Biasio, and C. Sette, “Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5′ splice site selection,” Nucleic Acids Research, vol. 42, no. 19, pp. 12070–12081, 2014. View at Publisher · View at Google Scholar
  85. M. P. Paronetto, T. Achsel, A. Massiello, C. E. Chalfant, and C. Sette, “The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x,” Journal of Cell Biology, vol. 176, no. 7, pp. 929–939, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Zhou, A. C. Ou, A. Cho, E. J. Benz Jr., and S.-C. Huang, “Novel splicing factor RBM25 modulates Bcl-x Pre-mRNA 5′ splice site selection,” Molecular and Cellular Biology, vol. 28, no. 19, pp. 5924–5936, 2008. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Pedrotti, R. Busà, C. Compagnucci, and C. Sette, “The RNA recognition motif protein RBM11 is a novel tissue-specific splicing regulator,” Nucleic Acids Research, vol. 40, no. 3, pp. 1021–1032, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Massiello, J. R. Roesser, and C. E. Chalfant, “SAP155 Binds to ceramide-responsive RNA cis-element 1 and regulates the alternative 5′ splice site selection of Bcl-x pre-mRNA,” The FASEB Journal, vol. 20, no. 10, pp. 1680–1682, 2006. View at Publisher · View at Google Scholar
  89. P. Cloutier, J. Toutant, L. Shkreta, S. Goekjian, T. Revil, and B. Chabot, “Antagonistic effects of the SRp30c protein and cryptic 5′ splice sites on the alternative splicing of the apoptotic regulator Bcl-x,” The Journal of Biological Chemistry, vol. 283, no. 31, pp. 21315–21324, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Revil, J. Pelletier, J. Toutant, A. Cloutier, and B. Chabot, “Heterogeneous nuclear ribonucleoprotein K represses the production of pro-apoptotic Bcl-xS splice isoform,” The Journal of Biological Chemistry, vol. 284, no. 32, pp. 21458–21467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. M. J. Moore, Q. Wang, C. J. Kennedy, and P. A. Silver, “An alternative splicing network links cell-cycle control to apoptosis,” Cell, vol. 142, no. 4, pp. 625–636, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. J. A. Bauman, S.-D. Li, A. Yang, L. Huang, and R. Kole, “Anti-tumor activity of splice-switching oligonucleotides,” Nucleic Acids Research, vol. 38, no. 22, pp. 8348–8356, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. D. R. Mercatante, J. L. Mohler, and R. Kole, “Cellular response to an antisense-mediated shift of Bcl-x pre-mRNA splicing and antineoplastic agents,” The Journal of Biological Chemistry, vol. 277, no. 51, pp. 49374–49382, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. O. Warburg, “On the origin of cancer cells,” Science, vol. 123, no. 3191, pp. 309–314, 1956. View at Publisher · View at Google Scholar · View at Scopus
  95. O. Warburg, “On respiratory impairment in cancer cells,” Science, vol. 124, no. 3215, pp. 269–270, 1956. View at Google Scholar · View at Scopus
  96. M. G. V. Heiden, L. C. Cantley, and C. B. Thompson, “Understanding the warburg effect: the metabolic requirements of cell proliferation,” Science, vol. 324, no. 5930, pp. 1029–1033, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. H. R. Christofk, M. G. Vander Heiden, M. H. Harris et al., “The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth,” Nature, vol. 452, no. 7184, pp. 230–233, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. W. Yang, Y. Xia, Y. Cao et al., “EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis,” Molecular Cell, vol. 48, no. 5, pp. 771–784, 2012. View at Publisher · View at Google Scholar · View at Scopus
  99. W. Yang, Y. Xia, D. Hawke et al., “PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis,” Cell, vol. 150, no. 4, pp. 685–696, 2012. View at Publisher · View at Google Scholar · View at Scopus
  100. C. V. Clower, D. Chatterjee, Z. Wang, L. C. Cantley, M. G. V. Heidena, and A. R. Krainer, “The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 5, pp. 1894–1899, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. C. J. David, M. Chen, M. Assanah, P. Canoll, and J. L. Manley, “HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer,” Nature, vol. 463, no. 7279, pp. 364–368, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Fodale, M. Pierobon, L. Liotta, and E. Petricoin, “Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance?” Cancer Journal, vol. 17, no. 2, pp. 89–95, 2011. View at Publisher · View at Google Scholar · View at Scopus
  103. Y. Wang, J. L. Dean, E. K. A. Millar et al., “Cyclin D1b is aberrantly regulated in response to therapeutic challenge and promotes resistance to estrogen antagonists,” Cancer Research, vol. 68, no. 14, pp. 5628–5638, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. J. W. Lee, Y. H. Soung, S. H. Seo et al., “Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas,” Clinical Cancer Research, vol. 12, no. 1, pp. 57–61, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. P. Stephens, C. Hunter, G. Bignell et al., “Lung cancer: intragenic ERBB2 kinase mutations in tumours,” Nature, vol. 431, no. 7008, pp. 525–526, 2004. View at Google Scholar
  106. C. I. Zito, D. Riches, J. Kolmakova, J. Simons, M. Egholm, and D. F. Stern, “Direct resequencing of the complete ERBB2 coding sequence reveals an absence of activating mutations in ERBB2 amplified breast cancer,” Genes Chromosomes and Cancer, vol. 47, no. 7, pp. 633–638, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. F. Castiglioni, E. Tagliabue, M. Campiglio, S. M. Pupa, A. Balsari, and S. Ménard, “Role of exon-16-deleted HER2 in breast carcinomas,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 221–232, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. K. Y. Kwong and M. C. Hung, “A novel splice variant of HER2 with increased transformation activity,” Molecular Carcinogenesis, vol. 23, no. 2, pp. 62–68, 1998. View at Google Scholar
  109. P. M. Siegel, E. D. Ryan, R. D. Cardiff, and W. J. Muller, “Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer,” The EMBO Journal, vol. 18, no. 8, pp. 2149–2164, 1999. View at Publisher · View at Google Scholar · View at Scopus
  110. D. Mitra, M. J. Brumlik, S. U. Okamgba et al., “An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance,” Molecular Cancer Therapeutics, vol. 8, no. 8, pp. 2152–2162, 2009. View at Publisher · View at Google Scholar · View at Scopus
  111. W. L. Perry III, R. L. Shepard, J. Sampath et al., “Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed—a phenotype partially reversed by selective estrogen receptor modulators,” Cancer Research, vol. 65, no. 15, pp. 6593–6600, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Sampath, P. R. Long, R. L. Shepard et al., “Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells,” The American Journal of Pathology, vol. 163, no. 5, pp. 1781–1790, 2003. View at Publisher · View at Google Scholar · View at Scopus
  113. A. M. Al-Ayoubi, H. Zheng, Y. Liu, T. Bai, and S. T. Eblen, “Mitogen-activated protein kinase phosphorylation of splicing factor 45 (SPF45) regulates SPF45 alternative splicing site utilization, proliferation, and cell adhesion,” Molecular and Cellular Biology, vol. 32, no. 14, pp. 2880–2893, 2012. View at Publisher · View at Google Scholar · View at Scopus
  114. L. Corsini, S. Bonnal, J. Basquin et al., “U2AF-homology motif interactions are required for alternative splicing regulation by SPF45,” Nature Structural and Molecular Biology, vol. 14, no. 7, pp. 620–629, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. Y. Liu, L. Conaway, J. Rutherford Bethard et al., “Phosphorylation of the alternative mRNA splicing factor 45 (SPF45) by Clk1 regulates its splice site utilization, cell migration and invasion,” Nucleic Acids Research, vol. 41, no. 9, pp. 4949–4962, 2013. View at Publisher · View at Google Scholar · View at Scopus
  116. S. M. Dehm, L. J. Schmidt, H. V. Heemers, R. L. Vessella, and D. J. Tindall, “Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance,” Cancer Research, vol. 68, no. 13, pp. 5469–5477, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. T. Sugiyama, Y. Nishio, T. Kishimoto, and S. Akira, “Identification of alternative splicing form of stat2,” FEBS Letters, vol. 381, no. 3, pp. 191–194, 1996. View at Publisher · View at Google Scholar · View at Scopus
  118. N. Zhang and Y.-W. He, “An essential role for c-FLIP in the efficient development of mature T lymphocytes,” The Journal of Experimental Medicine, vol. 202, no. 3, pp. 395–404, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. R. Busà, R. Geremia, and C. Sette, “Genotoxic stress causes the accumulation of the splicing regulator Sam68 in nuclear foci of transcriptionally active chromatin,” Nucleic Acids Research, vol. 38, no. 9, pp. 3005–3018, 2010. View at Publisher · View at Google Scholar · View at Scopus
  120. R. Busà, M. P. Paronetto, D. Farini et al., “The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells,” Oncogene, vol. 26, no. 30, pp. 4372–4382, 2007. View at Publisher · View at Google Scholar · View at Scopus
  121. M. P. Paronetto, B. Miñana, and J. Valcárcel, “The Ewing sarcoma protein regulates DNA damage-induced alternative splicing,” Molecular Cell, vol. 43, no. 3, pp. 353–368, 2011. View at Publisher · View at Google Scholar · View at Scopus
  122. L. Adesso, S. Calabretta, F. Barbagallo et al., “Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway,” Oncogene, vol. 32, no. 23, pp. 2848–2857, 2013. View at Publisher · View at Google Scholar · View at Scopus
  123. A. Maimon, M. Mogilevsky, A. Shilo et al., “Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation,” Cell Reports, vol. 7, no. 2, pp. 501–513, 2014. View at Publisher · View at Google Scholar · View at Scopus
  124. K. Lenos, A. M. Grawenda, K. Lodder et al., “Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer,” Cancer Research, vol. 72, no. 16, pp. 4074–4084, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. J. C. Shultz, R. W. Goehe, C. S. Murudkar et al., “SRSF1 regulates the alternative splicing of caspase 9 via a novel intronic splicing enhancer affecting the chemotherapeutic sensitivity of non-small cell lung cancer cells,” Molecular Cancer Research, vol. 9, no. 7, pp. 889–900, 2011. View at Publisher · View at Google Scholar · View at Scopus
  126. Z. Wang, H. Y. Jeon, F. Rigo, C. F. Bennett, and A. R. Krainer, “Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides,” Open Biology, vol. 2, no. 10, article 120133, 2012. View at Publisher · View at Google Scholar · View at Scopus
  127. F. Rigo, S. J. Chun, D. A. Norris et al., “Pharmacology of a central nervous system delivered 2′-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates,” Journal of Pharmacology and Experimental Therapeutics, vol. 350, no. 1, pp. 46–55, 2014. View at Publisher · View at Google Scholar