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Alternative splicing in cancer: implications for biology and therapy

Oncogene volume 34, pages 1–14 (2015)Cite this article

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Abstract

Alternative splicing has critical roles in normal development and can promote growth and survival in cancer. Aberrant splicing, the production of noncanonical and cancer-specific mRNA transcripts, can lead to loss-of-function in tumor suppressors or activation of oncogenes and cancer pathways. Emerging data suggest that aberrant splicing products and loss of canonically spliced variants correlate with stage and progression in malignancy. Here, we review the splicing landscape of TP53, BARD1 and AR to illuminate roles for alternative splicing in cancer. We also examine the intersection between alternative splicing pathways and novel therapeutic approaches.

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References

  1. Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008; 40: 1413–1415.

    Article  CAS  PubMed  Google Scholar 

  2. Burge CS, Tuschl T, Sharp PA . Splicing of precursors to mRNAs by the spliceosomes. In: Gesteland RF, Cech TR, Atkins JF (eds) RNA World Second edn. Cold Spring Harbor Laboratory Press, Woodbury, NY, 1999, pp 525–560.

    Google Scholar 

  3. Chen M, Manley J . Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 2009; 10: 741–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wahl M, Will C, Lührmann R . The spliceosome: design principles of a dynamic RNP Machine. Cell 2009; 136: 701–718.

    Article  CAS  PubMed  Google Scholar 

  5. Keren H, Lev-Maor G, Ast G . Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 2010; 11: 345–355.

    Article  CAS  PubMed  Google Scholar 

  6. Ellis JD, Barrios-Rodiles M, Çolak R, Irimia M, Kim T, Calarco JA et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell 2012; 46: 884–892.

    Article  CAS  PubMed  Google Scholar 

  7. Wu J, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S et al. Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. Proc Natl Acad Sci USA 2010; 107: 5254–5259.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kalsotra A, Cooper TA . Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet 2011; 12: 715–729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heyd F, Lynch K . DEGRADE, MOVE, REGROUP: signaling control of splicing proteins. Trends Biochem Sci 2011; 36: 397–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xu Q . Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res 2003; 31: 5635–5643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hui L, Zhang X, Wu X, Lin Z, Wang Q, Li Y et al. Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment. Oncogene 2004; 23: 3013–3023.

    Article  CAS  PubMed  Google Scholar 

  12. Venables J, Klinck R, Koh C, Gervais-Bird J, Bramard A, Inkel L et al. Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 2009; 16: 670–676.

    Article  CAS  PubMed  Google Scholar 

  13. Boise L, González-García M, Postema C, Ding L, Lindsten T, Turka L et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74: 597–608.

    Article  CAS  PubMed  Google Scholar 

  14. Xerri L, Parc P, Brousset P, Schlaifer D, Hassoun J, Reed J et al. Predominant expression of the long isoform of Bcl-x (Bcl-xL) in human lymphomas. Br J Haematol 1996; 92: 900–906.

    Article  CAS  PubMed  Google Scholar 

  15. Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H . Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology 2001; 34: 55–61.

    Article  CAS  PubMed  Google Scholar 

  16. Bouillet P, O’Reilly LA . CD95, BIM and T cell homeostasis. Nat Rev Immunol 2009; 9: 514–519.

    Article  CAS  PubMed  Google Scholar 

  17. Cascino I, Fiucci G, Papoff G, Ruberti G . Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol 1995; 154: 2706–2713.

    CAS  PubMed  Google Scholar 

  18. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 1994; 263: 1759–1762.

    Article  CAS  PubMed  Google Scholar 

  19. Liu JH, Wei S, Lamy T, Li Y, Epling-Burnette PK, Djeu JY et al. Blockade of Fas-dependent apoptosis by soluble Fas in LGL leukemia. Blood 2002; 100: 1449–1453.

    CAS  PubMed  Google Scholar 

  20. Sheen-Chen S-M, Chen H-S, Eng H-L, Chen W-J . Circulating soluble Fas in patients with breast cancer. World J Surg 2003; 27: 10–13.

    Article  PubMed  Google Scholar 

  21. Kondera-Anasz Z, Mielczarek-Palacz A, Sikora J . Soluble Fas receptor and soluble Fas ligand in the serum of women with uterine tumors. Apoptosis 2005; 10: 1143–1149.

    Article  CAS  PubMed  Google Scholar 

  22. Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

    Article  CAS  PubMed  Google Scholar 

  23. Noguchi T, Inoue H, Tanaka T . The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem 1986; 261: 13807–13812.

    CAS  PubMed  Google Scholar 

  24. Mazurek S, Boschek C, Hugo F, Eigenbrodt E . Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol 2005; 15: 300–308.

    Article  CAS  PubMed  Google Scholar 

  25. Christofk HR, vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008; 452: 230–233.

    Article  CAS  PubMed  Google Scholar 

  26. David CJ, Manley JL . Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 2010; 24: 2343–2364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lane DP, Crawford LV . T antigen is bound to a host protein in SV40-transformed cells. Nature 1979; 278: 261–263.

    Article  CAS  PubMed  Google Scholar 

  28. Linzer D, Levine A . Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 1979; 17: 43–52.

    Article  CAS  PubMed  Google Scholar 

  29. Finlay C, Hinds P, Levine A . The p53 proto-oncogene can act as a suppressor of transformation. Cell 1989; 57: 1083–1093.

    Article  CAS  PubMed  Google Scholar 

  30. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 1989; 244: 217–221.

    Article  CAS  PubMed  Google Scholar 

  31. Levine AJ, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer 2009; 9: 749–758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fields S, Jang SK . Presence of a potent transcription activating sequence in the p53 protein. Science 1990; 249: 1046–1049.

    Article  CAS  PubMed  Google Scholar 

  33. Raycroft L, Wu HY, Lozano G . Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 1990; 249: 1049–1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M . Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 1991; 352: 345–347.

    Article  CAS  PubMed  Google Scholar 

  35. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J et al. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci USA 1992; 89: 4495–4499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Serrano M, Lin A, McCurrach M, Beach D, Lowe S . Oncogenic Ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593–602.

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Blandino G, Oren M, Givol D . Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene 1998; 17: 1923–1930.

    Article  CAS  PubMed  Google Scholar 

  38. Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 2000; 404: 42–49.

    Article  CAS  PubMed  Google Scholar 

  39. Vogelstein B, Lane D, Levine A . Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  40. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B . Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 1993; 362: 857–860.

    Article  CAS  PubMed  Google Scholar 

  41. Haupt Y, Maya R, Kazaz A, Oren M . Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296–299.

    Article  CAS  PubMed  Google Scholar 

  42. Wu X, Bayle J, Olson D, Levine A . The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126–1132.

    Article  CAS  PubMed  Google Scholar 

  43. Brosh R, Rotter V . When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 2009; 9: 701–713.

    Article  CAS  PubMed  Google Scholar 

  44. Arai N, Nomura D, Yokota K, Wolf D, Brill E, Shohat O et al. Immunologically distinct p53 molecules generated by alternative splicing. Mol Cell Biol 1986; 6: 3232–3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Matlashewski G, Pim D, Banks L, Crawford L . Alternative splicing of human p53 transcripts. Oncogene Res 1987; 1: 77–85.

    CAS  PubMed  Google Scholar 

  46. Flaman JM, Waridel F, Estreicher A, Vannier A, Limacher JM, Gilbert D et al. The human tumour suppressor gene p53 is alternatively spliced in normal cells. Oncogene 1996; 12: 813–818.

    CAS  PubMed  Google Scholar 

  47. Courtois S, Verhaegh G, North S, Luciani M-G, Lassus P, Hibner U et al. DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 2002; 21: 6722–6728.

    Article  CAS  PubMed  Google Scholar 

  48. Bourdon J-C, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev 2005; 19: 2122–2137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ray PS, Grover R, Saumitra, Das S . Two internal ribosome entry sites mediate the translation of p53 isoforms. EMBO Rep 2006; 7: 404–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Candeias MM, Powell DJ, Roubalova E, Apcher S, Bourougaa K, Vojtesek B et al. Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene 2006; 25: 6936–6947.

    Article  CAS  PubMed  Google Scholar 

  51. Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L, Benchimol S . Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J 1984; 3: 3257–3262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fujita K, Mondal A, Horikawa I, Nguyen G, Kumamoto K, Sohn J et al. p53 isoforms |[Delta]|133p53 and p53|[beta]| are endogenous regulators of replicative cellular senescence. Nat Cell Biol 2009; 11: 1135–1142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hofstetter G, Berger A, Fiegl H, Slade N, Zorić A, Holzer B et al. Alternative splicing of p53 and p73: the novel p53 splice variant p53δ is an independent prognostic marker in ovarian cancer. Oncogene 2010; 29: 1997–2004.

    Article  CAS  PubMed  Google Scholar 

  54. Murray-Zmijewski F, Lane D . Bourdon J-C. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 2006; 13: 962–972.

    Article  CAS  PubMed  Google Scholar 

  55. Marcel V, Vijayakumar V, Fernández-Cuesta L, Hafsi H, Sagne C, Hautefeuille A et al. p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter. Oncogene 2010; 29: 2691–2700.

    Article  CAS  PubMed  Google Scholar 

  56. Chen J, Ng S, Chang C, Zhang Z, Bourdon J, Lane D et al. p53 isoform 113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes Dev 2009; 23: 278–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brady CA, Jiang D, Mello SS, Johnson TM, Jarvis LA, Kozak MM et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 2011; 145: 571–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ghosh A, Stewart D, Matlashewski G . Regulation of human p53 activity and cell localization by alternative splicing. Mol Cell Biol 2004; 24: 7987–7997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hafsi H, Lyon F, Santos-Silva D, Courtois-Cox S, Hainaut P, Ecully 69130. Effects of Δ40p53, an isoform of p53 lacking the N-terminus, on transactivation capacity of the tumor suppressor protein p53. BMC Cancer 2013; 13: 134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Holmila R, Fouquet C, Cadranel J, Zalcman G, Soussi T . Splice mutations in the p53 gene: case report and review of the literature. Hum Mutat 2003; 21: 101–102.

    Article  CAS  PubMed  Google Scholar 

  61. Bourdon J-C, Khoury MP, Diot A, Baker L, Fernandes K, Aoubala M et al. p53 mutant breast cancer patients expressing p53γ have as good a prognosis as wild-type p53 breast cancer patients. Breast Cancer Res 2011; 13: R7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Avery-Kiejda K, Zhang X, Adams L, Scott R, Vojtesek B, Lane D et al. Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin. Clin Cancer Res 2008; 14: 1659–1668.

    Article  CAS  PubMed  Google Scholar 

  63. Marabese M, Marchini S, Marrazzo E, Mariani P, Cattaneo D, Fossati R et al. Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer. Eur J Cancer 2008; 44: 131–141.

    Article  CAS  PubMed  Google Scholar 

  64. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.

    Article  CAS  PubMed  Google Scholar 

  65. Chen S, Parmigiani G . Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007; 25: 1329–1333.

    Article  PubMed  Google Scholar 

  66. Wu L, Wang Z, Tsan J, Spillman M, Phung A, Xu X et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 1996; 14: 430–440.

    Article  CAS  PubMed  Google Scholar 

  67. The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff [Internet]. (Accessed on 10 June 2013, available from http://www.hgmd.org/.

  68. Karppinen S-M, Heikkinen K, Rapakko K, Winqvist R . Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J Med Genet 2004; 41: e114.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ghimenti C, Sensi E, Presciuttini S, Brunetti I, Conte P, Bevilacqua G et al. Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosom Cancer 2002; 33: 235–242.

    Article  CAS  PubMed  Google Scholar 

  70. Thai TH, du F, Tsan JT, Jin Y, Phung A, Spillman MA et al. Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet 1998; 7: 195–202.

    Article  CAS  PubMed  Google Scholar 

  71. Irminger-Finger I, Soriano JV, Vaudan G, Montesano R, Sappino AP . In vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells. J Cell Biol 1998; 143: 1329–1339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Irminger-Finger I, Leung W-C, Li J, Dubois-Dauphin M, Harb J, Feki A et al. Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis. Mol Cell 2001; 8: 1255–1266.

    Article  CAS  PubMed  Google Scholar 

  73. McCarthy E, Celebi J, Baer R, Ludwig T . Loss of Bard1, the heterodimeric partner of the brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol Cell Biol 2003; 23: 5056–5063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Irminger-Finger I, Jefford C . Is there more to BARD1 than BRCA1? Nat Rev Cancer 2006; 6: 382–391.

    Article  CAS  PubMed  Google Scholar 

  75. Capasso M, Devoto M, Hou C, Asgharzadeh S, Glessner JT, Attiyeh EF et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet 2009; 41: 718–723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang K, Diskin S, Zhang H, Attiyeh E, Winter C, Hou C et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 2010; 469: 216–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Capasso M, Diskin S, Totaro F, Longo L, Mariano M, Russo R et al. Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis 2013; 34: 605–611.

    Article  CAS  PubMed  Google Scholar 

  78. Feki A, Jefford C, Berardi P, Wu J-Y, Cartier L, Krause K-H et al. BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 2005; 24: 3726–3736.

    Article  CAS  PubMed  Google Scholar 

  79. Tsuzuki M, Wu W, Nishikawa H, Hayami R, Oyake D, Yabuki Y et al. A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. Cancer Lett 2006; 233: 108–116.

    Article  CAS  PubMed  Google Scholar 

  80. Wu J-Y, Vlastos A-T, Pelte M-F, Caligo M-A, Bianco A, Krause K-H et al. Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. Int J Cancer 2006; 118: 1215–1226.

    Article  CAS  PubMed  Google Scholar 

  81. Scully R, Chen J, Ochs R, Keegan K, Hoekstra M, Feunteun J et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 1997; 90: 425–435.

    Article  CAS  PubMed  Google Scholar 

  82. Jefford C, Feki A, Harb J, Krause K-H, Irminger-Finger I . Nuclear—cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene 2004; 23: 3509–3520.

    Article  CAS  PubMed  Google Scholar 

  83. Li L, Ryser S, Dizin E, Pils D, Krainer M, Jefford CE et al. Oncogenic BARD1 isoforms expressed in gynecological cancers. Cancer Res 2007; 67: 11876–11885.

    Article  CAS  PubMed  Google Scholar 

  84. Ryser S, Dizin E, Jefford C, Delaval B, Gagos S, Christodoulidou A et al. Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1 scaffolds Aurora B and BRCA2. Cancer Res 2009; 69: 1125–1134.

    Article  CAS  PubMed  Google Scholar 

  85. Dizin E, Irminger-Finger I . Negative feedback loop of BRCA1—BARD1 ubiquitin ligase on estrogen receptor alpha stability and activity antagonized by cancer-associated isoform of BARD1. Int J Biochem Cell Biol 2010; 42: 693–700.

    Article  CAS  PubMed  Google Scholar 

  86. Sporn J, Hothorn T, Jung B . BARD1 expression predicts outcome in colon cancer. Clin Cancer Res 2011; 17: 5451–5462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang Y-Q, Pilyugin M, Kuester D, Leoni VP, Li L, Casula G et al. Expression of oncogenic BARD1 isoforms affects colon cancer progression and correlates with clinical outcome. Br J Cancer 2012; 107: 675–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang Y-Q, Bianco A, Malkinson AM, Leoni VP, Frau G, De Rosa N et al. BARD1: an independent predictor of survival in non-small cell lung cancer. Int J Cancer 2012; 131: 83–94.

    Article  CAS  PubMed  Google Scholar 

  89. Bosse K, Diskin S, Cole K, Wood A, Schnepp R, Norris G et al. Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res 2012; 72: 2068–2078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Evans RM . The steroid and thyroid hormone receptor superfamily. Science 1988; 240: 889–895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Taplin M-E . Drug Insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol 2007; 4: 236–244.

    Article  CAS  PubMed  Google Scholar 

  92. Knudsen KE, Scher HI . Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 2009; 15: 4792–4798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shang Y, Myers M, Brown M . Formation of the androgen receptor transcription complex. Mol Cell 2002; 9: 601–610.

    Article  CAS  PubMed  Google Scholar 

  94. Lubahn DB, Brown TR, Simental JA, Higgs HN, Migeon CJ, Wilson EM et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity. Proc Natl Acad Sci USA 1989; 86: 9534–9538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shaffer PL, Jivan A, Dollins DE, Claessens F, Gewirth DT . Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci USA 2004; 101: 4758–4763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem 2000; 275: 26164–26171.

    Article  CAS  PubMed  Google Scholar 

  97. Ahrens-Fath I, Politz O, Geserick C, Haendler B . Androgen receptor function is modulated by the tissue-specific AR45 variant. FEBS J 2005; 272: 74–84.

    Article  CAS  PubMed  Google Scholar 

  98. Ikonen T, Palvimo J, Jänne O . Heterodimerization is mainly responsible for the dominant negative activity of amino-terminally truncated rat androgen receptor forms. FEBS Lett 1998; 430: 393–396.

    Article  CAS  PubMed  Google Scholar 

  99. Jenster G, Korput H, Vroonhoven C, Kwast T, Trapman J, Brinkmann A et al. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 1991; 5: 1396–1404.

    Article  CAS  PubMed  Google Scholar 

  100. Huggins C, Hodges CV . Studies on prostatic cancer. Cancer Res 1941; 1: 293–297.

    CAS  Google Scholar 

  101. Attard G, Reid A, Olmos D, Bono J . Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res 2009; 69: 4937–4940.

    Article  CAS  PubMed  Google Scholar 

  102. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: 787–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995; 9: 401–406.

    Article  CAS  PubMed  Google Scholar 

  104. Brinkmann AO . Molecular basis of androgen insensitivity. Mol Cell Endocrinol 2001; 179: 105–109.

    Article  CAS  PubMed  Google Scholar 

  105. Ris-Stalpers C, Verleun-Mooijman MC, de Blaeij TJ, Degenhart HJ, Trapman J, Brinkmann AO . Differential splicing of human androgen receptor pre-mRNA in X-linked Reifenstein syndrome, because of a deletion involving a putative branch site. Am J Hum Genet 1994; 54: 609–617.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lim J, Ghadessy FJ, Yong EL . A novel splice site mutation in the androgen receptor gene results in exon skipping and a non-functional truncated protein. Mol Cell Endocrinol 1997; 131: 205–210.

    Article  CAS  PubMed  Google Scholar 

  107. Hellwinkel OJ-C, Bull K, Holterhus P-M, Homburg N, Struve D, Hiort O . Complete androgen insensitivity caused by a splice donor site mutation in intron 2 of the human androgen receptor gene resulting in an exon 2-lacking transcript with premature stop-codon and reduced expression. J Steroid Biochem Mol Biol 1999; 68: 1–9.

    Article  CAS  PubMed  Google Scholar 

  108. Hellwinkel OJ, Holterhus PM, Struve D, Marschke C, Homburg N, Hiort O . A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants. J Clin Endocrinol Metab 2001; 86: 2569–2575.

    CAS  PubMed  Google Scholar 

  109. Brüggenwirth HT, Boehmer AL, Ramnarain S, Verleun-Mooijman MC, Satijn DP, Trapman J et al. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation. Am J Hum Genet 1997; 61: 1067–1077.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Tepper CG, Boucher DL, Ryan PE, Ma A-H, Xia L, Lee L-F et al. Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Cancer Res 2002; 62: 6606–6614.

    CAS  PubMed  Google Scholar 

  111. Libertini S, Tepper C, Rodriguez V, Asmuth D, Kung H, Mudryj M . Evidence for calpain-mediated androgen receptor cleavage as a mechanism for androgen independence. Cancer Res 2007; 67: 9001–9005.

    Article  CAS  PubMed  Google Scholar 

  112. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ . Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 2008; 68: 5469–5477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Marcias G, Erdmann E, Lapouge GG, Siebert C, Barthélémy P, Duclos B et al. Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line. Hum Mutat 2010; 31: 74–80.

    Article  CAS  PubMed  Google Scholar 

  114. Hu R, Dunn T, Wei S, Isharwal S, Veltri R, Humphreys E et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009; 69: 16–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen HH et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 2009; 69: 2305–2313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jagla M, Feve M, Kessler P, Lapouge G, Erdmann E, Serra S et al. A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions. Endocrinology 2007; 148: 4334–4343.

    Article  CAS  PubMed  Google Scholar 

  117. Sun S, Sprenger CCT, Vessella RL, Haugk K, Soriano K, Mostaghel EA et al. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 2010; 120: 2715–2730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hu R, Isaacs WB, Luo J . A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate 2011; 71: 1656–1667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang X, Morrissey C, Sun S, Ketchandji M, Nelson PS, True LD et al. Androgen receptor variants occur frequently in castration resistant prostate cancer metastases. PLoS One 2011; 6: e27970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A et al. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA 2010; 107: 16759–16765.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Chan SC, Li Y, Dehm SM . Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem 2012; 287: 19736–19749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cocquerelle C, Daubersies P, Majérus MA, Kerckaert JP, Bailleul B . Splicing with inverted order of exons occurs proximal to large introns. EMBO J 1992; 11: 1095–1098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO . Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. Preiss T (ed) PLoS One 2012; 7: e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Dreyfuss G, Matunis M, Pinol-Roma S, Burd C . hnRNP Proteins and the biogenesis of mRNA. Annu Rev Biochem 1993; 62: 289–321.

    Article  CAS  PubMed  Google Scholar 

  125. Manley J, Tacke R . SR proteins and splicing control. Genes Dev 1996; 10: 1569–1579.

    Article  CAS  PubMed  Google Scholar 

  126. Wu JY, Maniatis T . Specific interactions between proteins implicated in splice site selection and regulated alternative splicing. Cell 1993; 75: 1061–1070.

    Article  CAS  PubMed  Google Scholar 

  127. Graveley BR, Hertel KJ, Maniatis T . The role of U2AF35 and U2AF65 in enhancer-dependent splicing. RNA 2001; 7: 806–818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Matlin AJ, Clark F, Smith CWJ, Clark C . Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005; 6: 386–398.

    Article  CAS  PubMed  Google Scholar 

  129. Mayeda A, Helfman DM, Krainer AR . Modulation of exon skipping and inclusion by heterogeneous nuclear ribonucleoprotein A1 and pre-mRNA splicing factor SF2/ASF. Mol Cell Biol 1993; 13: 2993–3001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Crawford JB, Patton JG . Activation of alpha-tropomyosin exon 2 is regulated by the SR protein 9G8 and heterogeneous nuclear ribonucleoproteins H and F. Mol Cell Biol 2006; 26: 8791–8802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Li X, Manley J . Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 2005; 122: 365–378.

    Article  CAS  PubMed  Google Scholar 

  132. Karni R, Stanchina E, Lowe S, Sinha R, Mu D, Krainer A et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007; 14: 185–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Karni R, Hippo Y, Lowe S, Krainer A . The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci USA 2008; 105: 15323–15327.

  134. Tang Y, Horikawa I, Ajiro M, Robles AI, Fujita K, Mondal AM et al. Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence. Oncogene 2013; 32: 2792–2798.

    Article  CAS  PubMed  Google Scholar 

  135. David C, Chen M, Assanah M, Canoll P, Manley J . HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2009; 463: 364–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B et al. EGFR mutation-induced alternative splicing of max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 2013; 17: 1000–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Boukakis G, Patrinou-Georgoula M, Lekarakou M, Valavanis C et alBiotechnology I Hospital P. Deregulated expression of hnRNP A/B proteins in human non-small cell lung cancer: parallel assessment of protein and mRNA levels in paired tumour/non-tumour tissues. BMC Cancer 2010; 10: 434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ghigna C, Moroni M, Porta C, Riva S, Biamonti G . Altered expression of heterogeneous nuclear ribonucleoproteins and SR factors in human colon adenocarcinomas. Cancer Res 1998; 58: 5818–5824.

    CAS  PubMed  Google Scholar 

  139. Piekielko-Witkowska A, Wiszomirska H, Wojcicka A, Poplawski P, Boguslawska J, Tanski Z et al. Disturbed expression of splicing factors in renal cancer affects alternative splicing of apoptosis regulators, oncogenes, and tumor suppressors. PLoS One 2010; 5: e13690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lefave CV, Squatrito M, Vorlova S, Rocco GL, Brennan CW, Holland EC et al. Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas. EMBO J 2011; 30: 4084–4097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ponta H, Sherman L, Herrlich P . CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003; 4: 33–45.

    Article  CAS  PubMed  Google Scholar 

  142. Cheng C, Sharp P . Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion. Mol Cell Biol 2005; 26: 362–370.

    Article  CAS  Google Scholar 

  143. Cappellari M, Bielli P, Paronetto M, Ciccosanti F, Fimia G, Saarikettu J et al. The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells. Oncogene 2013. 1–9.

  144. Guo X, Branch P, Chen Q-R, Song Y, Wei J et alSAIC-Frederick. Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status. BMC Med Genomics 2011; 4: 35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Thorsen K, Sorensen K, Brems-Eskildsen A, Modin C, Gaustadnes M, Hein A et al. Alternative splicing in colon, bladder, and prostate cancer identified by exon array analysis. Mol Cell Proteomics 2008; 7: 1214–1224.

    Article  CAS  PubMed  Google Scholar 

  146. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478: 64–69.

    Article  CAS  PubMed  Google Scholar 

  147. Druker B, Tamura S, Buchdunger E, Ohno S, Segal G, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr—Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  PubMed  Google Scholar 

  148. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wilson T, Fridly J, Yan Y, Penuel E, Burton L, Chan E et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian Z, Du J et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nazarian R, Shi H, Wang Q, Kong X, Koya R, Lee H et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468: 973–977.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480: 387–390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80: 155–165.

    Article  CAS  PubMed  Google Scholar 

  154. Lorson C, Rindt H, Shababi M . Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum Mol Genet 2010; 19: R111–R118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett C et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011; 478: 123–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Miller-Wideman M, Makkar N, Tran M, Isaac B, Biest N, Stonard R . Herboxidiene, a new herbicidal substance from Streptomyces chromofuscus A7847. Taxonomy, fermentation, isolation, physico-chemical and biological properties. J Antibiot (Tokyo) 1992; 45: 914–921.

    Article  CAS  Google Scholar 

  157. Nakajima H, Sato B, Fujita T, Takase S, Terano H, Okuhara M . New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo) 1996; 49: 1196–1203.

    Article  CAS  Google Scholar 

  158. Sakai T, Sameshima T, Matsufuji M, Kawamura N, Dobashi K, Mizui Y . Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. J Antibiot (Tokyo) 2004; 57: 173–179.

    Article  CAS  Google Scholar 

  159. Bonnal S, Vigevani L, Valc| J, Vigevani J . The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 2012; 11: 847–859.

    Article  CAS  PubMed  Google Scholar 

  160. Webb TR, Joyner AS, Potter PM . The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. Drug Discov Today 2013; 18: 43–49.

    Article  CAS  PubMed  Google Scholar 

  161. Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol 2007; 3: 570–575.

    Article  CAS  PubMed  Google Scholar 

  162. Kaida D, Motoyoshi H, Tashiro E, Nojima T, Hagiwara M, Ishigami K et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol 2007; 3: 576–583.

    Article  CAS  PubMed  Google Scholar 

  163. Fan L, Lagisetti C, Edwards CC, Webb TR, Potter PM . Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing. ACS Chem Biol 2011; 6: 582–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Folco E, Coil K, Reed R . The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region. Genes Dev 2011; 25: 440–444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Furumai R, Uchida K, Komi Y, Yoneyama M, Ishigami K, Watanabe H et al. Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF. Cancer Sci 2010; 101: 2483–2489.

    Article  CAS  PubMed  Google Scholar 

  166. Corrionero A, Minana B, Valcarcel J . Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 2011; 25: 445–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhou Z, Licklider L, Gygi S, Reed R . Comprehensive proteomic analysis of the human spliceosome. Nature 2002; 419: 182–185.

    Article  CAS  PubMed  Google Scholar 

  168. Liu HX, Zhang M, Krainer AR . Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev 1998; 12: 1998–2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Liu HX, Chew SL, Cartegni L, Zhang MQ, Krainer AR . Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol Cell Biol 2000; 20: 1063–1071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Coulter LR, Landree MA, Cooper TA . Identification of a new class of exonic splicing enhancers by in vivo selection. Mol Cell Biol 1997; 17: 2143–2150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Fairbrother WG, Yeh R-F, Sharp PA, Burge CB . Predictive identification of exonic splicing enhancers in human genes. Science 2002; 297: 1007–1013.

    Article  CAS  PubMed  Google Scholar 

  172. Fairbrother W, Yeo G, Yeh R, Goldstein P, Mawson M, Sharp P et al. RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res 2004; 32 (Web Server): W187–W190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Yeo G, Hoon S, Venkatesh B, Burge CB . Variation in sequence and organization of splicing regulatory elements in vertebrate genes. Proc Natl Acad Sci USA 2004; 101: 15700–15705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Yeo GW, Nostrand EL, Van, Liang TY, Jolla C, Van Nostrand EL . Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements. PLoS Genet 2007; 3: e85.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Wang Y, Ma M, Xiao X, Wang Z . Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules. Nat Struct Mol Biol 2012; 19: 1044–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hong X, Scofield DG, Lynch M . Intron size, abundance, and distribution within untranslated regions of genes. Mol Biol Evol 2006; 23: 2392–2404.

    Article  CAS  PubMed  Google Scholar 

  177. Marcel V, Perrier S, Aoubala M, Ageorges S, Groves M, Diot A et al. Δ160p53 is a novel N-terminal p53 isoform encoded by Δ133p53 transcript. FEBS Lett 2010; 584: 4463–4468.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Clay Gustafson, Miller Huang and Erin Simonds for reviewing the manuscript. The Weiss lab is supported by NIH grants CA176287, CA82104, CA133091, CA102321, CA148699, CA159859, CA163155 and CA081403; and the CureSearch, Katie Dougherty, Pediatric Brain Tumor, St Baldricks and Samuel G Waxman Foundations.

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  1. Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA

    J Chen

  2. Department of Neurology, University of California, San Francisco, CA, USA

    J Chen & W A Weiss

  3. Department of Neurological Surgery and Pediatrics, University of California, San Francisco, CA, USA

    W A Weiss

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Chen, J., Weiss, W. Alternative splicing in cancer: implications for biology and therapy. Oncogene 34, 1–14 (2015). https://doi.org/10.1038/onc.2013.570

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