WIREs RNA

Volume 4, Issue 5 p. 547-566

Advanced Review

Alternative RNA splicing and cancer

Sali Liu,

Sali Liu

Search for more papers by this author

Chonghui Cheng,

Corresponding Author

Chonghui Cheng

Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Correspondence to: [email protected]Search for more papers by this author

Sali Liu,

Sali Liu

Search for more papers by this author

Chonghui Cheng,

Corresponding Author

Chonghui Cheng

Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Correspondence to: [email protected]Search for more papers by this author

First published: 13 June 2013

https://doi.org/10.1002/wrna.1178

Citations: 61

Conflict of interest: The authors have declared no conflicts of interest for this article.

Read the full text

About

PDF

Tools

Share a link

Email
Facebook
Twitter
LinkedIn
Reddit
Wechat

Abstract

Alternative splicing of pre-messenger RNA (mRNA) is a fundamental mechanism by which a gene can give rise to multiple distinct mRNA transcripts, yielding protein isoforms with different, even opposing, functions. With the recognition that alternative splicing occurs in nearly all human genes, its relationship with cancer-associated pathways has emerged as a rapidly growing field. In this review, we summarize recent findings that have implicated the critical role of alternative splicing in cancer and discuss current understandings of the mechanisms underlying dysregulated alternative splicing in cancer cells. WIREs RNA 2013, 4:547–566. doi: 10.1002/wrna.1178

This article is categorized under:

RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease

REFERENCES

1Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB. Alternative isoform regulation in human tissue transcriptomes. Nature 2008, 456: 470–476.
10.1038/nature07509
CASPubMedWeb of Science®Google Scholar
2Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008, 40: 1413–1415.
10.1038/ng.259
CASPubMedWeb of Science®Google Scholar
3Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 2010, 11: 345–355.
10.1038/nrg2776
CASPubMedWeb of Science®Google Scholar
4Alekseyenko AV, Kim N, Lee CJ. Global analysis of exon creation versus loss and the role of alternative splicing in 17 vertebrate genomes. RNA 2007, 13: 661–670.
10.1261/rna.325107
CASPubMedWeb of Science®Google Scholar
5Sugnet CW, Kent WJ, Ares M Jr, Haussler D. Transcriptome and genome conservation of alternative splicing events in humans and mice. Pac Symp Biocomput 2004: 66–77.

CASPubMedGoogle Scholar
6Jurica MS, Moore MJ. Pre-mRNA splicing: awash in a sea of proteins. Mol Cell 2003, 12: 5–14.
10.1016/S1097-2765(03)00270-3
CASPubMedWeb of Science®Google Scholar
7Maniatis T, Reed R. The role of small nuclear ribonucleoprotein particles in pre-mRNA splicing. Nature 1987, 325: 673–678.
10.1038/325673a0
CASPubMedWeb of Science®Google Scholar
8Will CL, Luhrmann R. Spliceosome structure and function. Cold Spring Harb Perspect Biol 2011, 3:a003707.
10.1101/cshperspect.a003707
CASPubMedWeb of Science®Google Scholar
9Fischer U, Englbrecht C, Chari A. Biogenesis of spliceosomal small nuclear ribonucleoproteins. WIREs RNA 2011, 2: 718–731.
10.1002/wrna.87
CASPubMedWeb of Science®Google Scholar
10Busch A, Hertel KJ. Evolution of SR protein and hnRNP splicing regulatory factors. WIREs RNA 2012, 3: 1–12.
10.1002/wrna.100
CASPubMedWeb of Science®Google Scholar
11Manley JL, Tacke R. SR proteins and splicing control. Genes Dev 1996, 10: 1569–1579.
10.1101/gad.10.13.1569
CASPubMedWeb of Science®Google Scholar
12Graveley BR. Sorting out the complexity of SR protein functions. RNA 2000, 6: 1197–1211.
10.1017/S1355838200000960
CASPubMedWeb of Science®Google Scholar
13Long JC, Caceres JF. The SR protein family of splicing factors: master regulators of gene expression. Biochem J 2009, 417: 15–27.
10.1042/BJ20081501
CASPubMedWeb of Science®Google Scholar
14Han SP, Tang YH, Smith R. Functional diversity of the hnRNPs: past, present and perspectives. Biochem J 2010, 430: 379–392.
10.1042/BJ20100396
CASPubMedWeb of Science®Google Scholar
15Martinez-Contreras R, Cloutier P, Shkreta L, Fisette JF, Revil T, Chabot B. hnRNP proteins and splicing control. Adv Exp Med Biol 2007, 623: 123–147.
10.1007/978-0-387-77374-2_8
PubMedWeb of Science®Google Scholar
16Garneau D, Revil T, Fisette JF, Chabot B. Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x. J Biol Chem 2005, 280: 22641–22650.
10.1074/jbc.M501070200
CASPubMedWeb of Science®Google Scholar
17Chou MY, Rooke N, Turck CW, Black DL. hnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. Mol Cell Biol 1999, 19: 69–77.
10.1128/MCB.19.1.69
CASPubMedWeb of Science®Google Scholar
18Buratti E, Stuani C, De Prato G, Baralle FE. SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer. Nucleic Acids Res 2007, 35: 4359–4368.
10.1093/nar/gkm444
CASPubMedWeb of Science®Google Scholar
19Lemaire R, Winne A, Sarkissian M, Lafyatis R. SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. Eur J Immunol 1999, 29: 823–837.
10.1002/(SICI)1521-4141(199903)29:03<823::AID-IMMU823>3.0.CO;2-C
CASPubMedWeb of Science®Google Scholar
20Gallego ME, Gattoni R, Stevenin J, Marie J, Expert-Bezancon A. The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the β-tropomyosin alternative exon 6A. EMBO J 1997, 16: 1772–1784.
10.1093/emboj/16.7.1772
CASPubMedWeb of Science®Google Scholar
21ten Dam GB, Zilch CF, Wallace D, Wieringa B, Beverley PC, Poels LG, Screaton GR. Regulation of alternative splicing of CD45 by antagonistic effects of SR protein splicing factors. J Immunol 2000, 164: 5287–5295.
10.4049/jimmunol.164.10.5287
PubMedWeb of Science®Google Scholar
22Wang Z, Burge CB. Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 2008, 14: 802–813.
10.1261/rna.876308
CASPubMedWeb of Science®Google Scholar
23Wang Y, Xiao X, Zhang J, Choudhury R, Robertson A, Li K, Ma M, Burge CB, Wang Z. A complex network of factors with overlapping affinities represses splicing through intronic elements. Nat Struct Mol Biol 2013, 20: 36–45.
10.1038/nsmb.2459
CASPubMedWeb of Science®Google Scholar
24Motta-Mena LB, Heyd F, Lynch KW. Context-dependent regulatory mechanism of the splicing factor hnRNP L. Mol Cell 2010, 37: 223–234.
10.1016/j.molcel.2009.12.027
CASPubMedWeb of Science®Google Scholar
25Zhang C, Zhang Z, Castle J, Sun S, Johnson J, Krainer AR, Zhang MQ. Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev 2008, 22: 2550–2563.
10.1101/gad.1703108
CASPubMedWeb of Science®Google Scholar
26Ule J, Stefani G, Mele A, Ruggiu M, Wang X, Taneri B, Gaasterland T, Blencowe BJ, Darnell RB. An RNA map predicting Nova-dependent splicing regulation. Nature 2006, 444: 580–586.
10.1038/nature05304
CASPubMedWeb of Science®Google Scholar
27Yu Y, Maroney PA, Denker JA, Zhang XH, Dybkov O, Luhrmann R, Jankowsky E, Chasin LA, Nilsen TW. Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 2008, 135: 1224–1236.
10.1016/j.cell.2008.10.046
CASPubMedWeb of Science®Google Scholar
28Hertel KJ. Combinatorial control of exon recognition. J Biol Chem 2008, 283: 1211–1215.
10.1074/jbc.R700035200
CASPubMedWeb of Science®Google Scholar
29House AE, Lynch KW. Regulation of alternative splicing: more than just the ABCs. J Biol Chem 2008, 283: 1217–1221.
10.1074/jbc.R700031200
CASPubMedWeb of Science®Google Scholar
30Smith CW, Valcarcel J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci 2000, 25: 381–388.
10.1016/S0968-0004(00)01604-2
CASPubMedWeb of Science®Google Scholar
31Matlin AJ, Clark F, Smith CW. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005, 6: 386–398.
10.1038/nrm1645
CASPubMedWeb of Science®Google Scholar
32Melton AA, Jackson J, Wang J, Lynch KW. Combinatorial control of signal-induced exon repression by hnRNP L and PSF. Mol Cell Biol 2007, 27: 6972–6984.
10.1128/MCB.00419-07
CASPubMedWeb of Science®Google Scholar
33Barash Y, Calarco JA, Gao W, Pan Q, Wang X, Shai O, Blencowe BJ, Frey BJ. Deciphering the splicing code. Nature 2010, 465: 53–59.
10.1038/nature09000
CASPubMedWeb of Science®Google Scholar
34Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 2003, 72: 291–336.
10.1146/annurev.biochem.72.121801.161720
CASPubMedWeb of Science®Google Scholar
35Buckanovich RJ, Posner JB, Darnell RB. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 1993, 11: 657–672.
10.1016/0896-6273(93)90077-5
CASPubMedWeb of Science®Google Scholar
36Polydorides AD, Okano HJ, Yang YY, Stefani G, Darnell RB. A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing. Proc Natl Acad Sci U S A 2000, 97: 6350–6355.
10.1073/pnas.110128397
CASPubMedWeb of Science®Google Scholar
37Markovtsov V, Nikolic JM, Goldman JA, Turck CW, Chou MY, Black DL. Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol Cell Biol 2000, 20: 7463–7479.
10.1128/MCB.20.20.7463-7479.2000
CASPubMedWeb of Science®Google Scholar
38Underwood JG, Boutz PL, Dougherty JD, Stoilov P, Black DL. Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals. Mol Cell Biol 2005, 25: 10005–10016.
10.1128/MCB.25.22.10005-10016.2005
CASPubMedWeb of Science®Google Scholar
39Jin Y, Suzuki H, Maegawa S, Endo H, Sugano S, Hashimoto K, Yasuda K, Inoue K. A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J 2003, 22: 905–912.
10.1093/emboj/cdg089
CASPubMedWeb of Science®Google Scholar
40Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP. ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 2009, 33: 591–601.
10.1016/j.molcel.2009.01.025
CASPubMedWeb of Science®Google Scholar
41Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB. CLIP identifies Nova-regulated RNA networks in the brain. Science 2003, 302: 1212–1215.
10.1126/science.1090095
CASPubMedWeb of Science®Google Scholar
42Zhang C, Frias MA, Mele A, Ruggiu M, Eom T, Marney CB, Wang H, Licatalosi DD, Fak JJ, Darnell RB. Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls. Science 2010, 329: 439–443.
10.1126/science.1191150
CASPubMedWeb of Science®Google Scholar
43Coutinho-Mansfield GC, Xue Y, Zhang Y, Fu XD. PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation. Genes Dev 2007, 21: 1573–1577.
10.1101/gad.1575607
CASPubMedWeb of Science®Google Scholar
44Dittmar KA, Jiang P, Park JW, Amirikian K, Wan J, Shen S, Xing Y, Carstens RP. Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol Cell Biol 2012, 32: 1468–1482.
10.1128/MCB.06536-11
CASPubMedWeb of Science®Google Scholar
45Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, Guo W, Xing Y, Carstens RP. An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 2010, 29: 3286–3300.
10.1038/emboj.2010.195
CASPubMedWeb of Science®Google Scholar
46Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH. An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat Struct Mol Biol 2009, 16: 130–137.
10.1038/nsmb.1545
CASPubMedWeb of Science®Google Scholar
47Okumura N, Yoshida H, Kitagishi Y, Nishimura Y, Matsuda S. Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer. Biochem Biophys Res Commun 2011, 413: 395–399.
10.1016/j.bbrc.2011.08.098
CASPubMedWeb of Science®Google Scholar
48Cohen JB, Broz SD, Levinson AD. Expression of the H-ras proto-oncogene is controlled by alternative splicing. Cell 1989, 58: 461–472.
10.1016/0092-8674(89)90427-3
CASPubMedWeb of Science®Google Scholar
49Reiter J, Maihle NJ. Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta. Ann N Y Acad Sci 2003, 995: 39–47.
10.1111/j.1749-6632.2003.tb03208.x
CASPubMedWeb of Science®Google Scholar
50Marcel V, Dichtel-Danjoy ML, Sagne C, Hafsi H, Ma D, Ortiz-Cuaran S, Olivier M, Hall J, Mollereau B, Hainaut P, et al. Biological functions of p53 isoforms through evolution: lessons from animal and cellular models. Cell Death Differ 2011, 18: 1815–1824.
10.1038/cdd.2011.120
CASPubMedWeb of Science®Google Scholar
51Reiter JL, Threadgill DW, Eley GD, Strunk KE, Danielsen AJ, Sinclair CS, Pearsall RS, Green PJ, Yee D, Lampland AL, et al. Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms. Genomics 2001, 71: 1–20.
10.1006/geno.2000.6341
CASPubMedWeb of Science®Google Scholar
52David CJ, Manley JL. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 2010, 24: 2343–2364.
10.1101/gad.1973010
CASPubMedWeb of Science®Google Scholar
53Ward AJ, Cooper TA. The pathobiology of splicing. J Pathol 2010, 220: 152–163.
10.1002/path.2649
CASPubMedWeb of Science®Google Scholar
54Skotheim RI, Nees M. Alternative splicing in cancer: noise, functional, or systematic? Int J Biochem Cell Biol 2007, 39: 1432–1449.
10.1016/j.biocel.2007.02.016
CASPubMedWeb of Science®Google Scholar
55Srebrow A, Kornblihtt AR. The connection between splicing and cancer. J Cell Sci 2006, 119: 2635–2641.
10.1242/jcs.03053
CASPubMedWeb of Science®Google Scholar
56Singh RK, Cooper TA. Pre-mRNA splicing in disease and therapeutics. Trends Mol Med 2012, 18: 472–482.
10.1016/j.molmed.2012.06.006
CASPubMedWeb of Science®Google Scholar
57Bauman JA, Kole R. Modulation of RNA splicing as a potential treatment for cancer. Bioeng Bugs 2011, 2: 125–128.
10.4161/bbug.2.3.15165
PubMedGoogle Scholar
58Spitali P, Aartsma-Rus A. Splice modulating therapies for human disease. Cell 2012, 148: 1085–1088.
10.1016/j.cell.2012.02.014
CASPubMedWeb of Science®Google Scholar
59Brinkman BM. Splice variants as cancer biomarkers. Clin Biochem 2004, 37: 584–594.
10.1016/j.clinbiochem.2004.05.015
CASPubMedWeb of Science®Google Scholar
60Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011, 144: 646–674.
10.1016/j.cell.2011.02.013
CASPubMedWeb of Science®Google Scholar
61Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiology (Bethesda) 2010, 25: 85–101.
10.1152/physiol.00045.2009
CASPubMedWeb of Science®Google Scholar
62Perona R. Cell signalling: growth factors and tyrosine kinase receptors. Clin Transl Oncol 2006, 8: 77–82.
10.1007/s12094-006-0162-1
CASPubMedGoogle Scholar
63Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 2009, 21: 177–184.
10.1016/j.ceb.2008.12.010
CASPubMedWeb of Science®Google Scholar
64Medema RH, de Vries-Smits AM, van der Zon GC, Maassen JA, Bos JL. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol 1993, 13: 155–162.
10.1128/MCB.13.1.155
CASPubMedWeb of Science®Google Scholar
65Cheng C, Yaffe MB, Sharp PA. A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev 2006, 20: 1715–1720.
10.1101/gad.1430906
CASPubMedWeb of Science®Google Scholar
66Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 2002, 16: 3074–3086.
10.1101/gad.242602
CASPubMedWeb of Science®Google Scholar
67Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H, Herrlich P. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 2001, 15: 968–980.
10.1101/gad.189601
CASPubMedWeb of Science®Google Scholar
68Konig H, Ponta H, Herrlich P. Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator. EMBO J 1998, 17: 2904–2913.
10.1093/emboj/17.10.2904
CASPubMedWeb of Science®Google Scholar
69Weg-Remers S, Ponta H, Herrlich P, Konig H. Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J 2001, 20: 4194–4203.
10.1093/emboj/20.15.4194
CASPubMedWeb of Science®Google Scholar
70Matter N, Herrlich P, Konig H. Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 2002, 420: 691–695.
10.1038/nature01153
CASPubMedWeb of Science®Google Scholar
71Cheng C, Sharp PA. Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion. Mol Cell Biol 2006, 26: 362–370.
10.1128/MCB.26.1.362-370.2006
CASPubMedWeb of Science®Google Scholar
72Zhao P, Damerow MS, Stern P, Liu AH, Sweet-Cordero A, Siziopikou K, Neilson JR, Sharp PA, Cheng C. CD44 promotes Kras-dependent lung adenocarcinoma. Oncogene (Epub ahead of print; December 3, 2012).

Web of Science®Google Scholar
73Howe D, Lynas C. The cyclin D1 alternative transcripts [a] and [b] are expressed in normal and malignant lymphocytes and their relative levels are influenced by the polymorphism at codon 241. Haematologica 2001, 86: 563–569.

CASPubMedWeb of Science®Google Scholar
74Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 2006, 25: 1620–1628.
10.1038/sj.onc.1209371
CASPubMedWeb of Science®Google Scholar
75Comstock CE, Augello MA, Benito RP, Karch J, Tran TH, Utama FE, Tindall EA, Wang Y, Burd CJ, Groh EM, et al. Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer. Clin Cancer Res 2009, 15: 5338–5349.
10.1158/1078-0432.CCR-08-2865
CASPubMedWeb of Science®Google Scholar
76Lu F, Gladden AB, Diehl JA. An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 2003, 63: 7056–7061.

CASPubMedWeb of Science®Google Scholar
77Paronetto MP, Cappellari M, Busa R, Pedrotti S, Vitali R, Comstock C, Hyslop T, Knudsen KE, Sette C. Alternative splicing of the cyclin D1 proto-oncogene is regulated by the RNA-binding protein Sam68. Cancer Res 2010, 70: 229–239.
10.1158/0008-5472.CAN-09-2788
CASPubMedWeb of Science®Google Scholar
78Olshavsky NA, Comstock CE, Schiewer MJ, Augello MA, Hyslop T, Sette C, Zhang J, Parysek LM, Knudsen KE. Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer Res 2010, 70: 3975–3984.
10.1158/0008-5472.CAN-09-3468
CASPubMedWeb of Science®Google Scholar
79Tang Y, Horikawa I, Ajiro M, Robles AI, Fujita K, Mondal AM, Stauffer JK, Zheng ZM, Harris CC. Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence. Oncogene (Epub ahead of print; July 9, 2012).

Google Scholar
80Fujita K, Mondal AM, Horikawa I, Nguyen GH, Kumamoto K, Sohn JJ, Bowman ED, Mathe EA, Schetter AJ, Pine SR, et al. p53 isoforms δ133p53 and p53β are endogenous regulators of replicative cellular senescence. Nat Cell Biol 2009, 11: 1135–1142.
10.1038/ncb1928
CASPubMedWeb of Science®Google Scholar
81Jia R, Li C, McCoy JP, Deng CX, Zheng ZM. SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance. Int J Biol Sci 2010, 6: 806–826.
10.7150/ijbs.6.806
CASPubMedWeb of Science®Google Scholar
82He X, Arslan AD, Pool MD, Ho TT, Darcy KM, Coon JS, Beck WT. Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer. Oncogene 2011, 30: 356–365.
10.1038/onc.2010.426
CASPubMedWeb of Science®Google Scholar
83Murray-Zmijewski F, Lane DP, Bourdon JC. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 2006, 13: 962–972.
10.1038/sj.cdd.4401914
CASPubMedWeb of Science®Google Scholar
84Wei J, Zaika E, Zaika A. p53 family: role of protein isoforms in human cancer. J Nucleic Acids 2012, 2012: 687359.
10.1155/2012/687359
CASPubMedGoogle Scholar
85Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature 2004, 432: 307–315.
10.1038/nature03098
CASPubMedWeb of Science®Google Scholar
86Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007, 26: 1324–1337.
10.1038/sj.onc.1210220
CASPubMedWeb of Science®Google Scholar
87Shultz JC, Chalfant CE. Caspase 9b: a new target for therapy in non-small-cell lung cancer. Expert Rev Anticancer Ther 2011, 11: 499–502.
10.1586/era.11.23
CASPubMedWeb of Science®Google Scholar
88Schwerk C, Schulze-Osthoff K. Regulation of apoptosis by alternative pre-mRNA splicing. Mol Cell 2005, 19: 1–13.
10.1016/j.molcel.2005.05.026
CASPubMedWeb of Science®Google Scholar
89Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 1994, 263: 1759–1762.
10.1126/science.7510905
CASPubMedWeb of Science®Google Scholar
90Cascino 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.
10.4049/jimmunol.154.6.2706
CASPubMedWeb of Science®Google Scholar
91Izquierdo JM, Majos N, Bonnal S, Martinez C, Castelo R, Guigo R, Bilbao D, Valcarcel J. Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Mol Cell 2005, 19: 475–484.
10.1016/j.molcel.2005.06.015
CASPubMedWeb of Science®Google Scholar
92Izquierdo JM. Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition. J Biol Chem 2008, 283: 19077–19084.
10.1074/jbc.M800017200
CASPubMedWeb of Science®Google Scholar
93Izquierdo JM. 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 Res 2010, 38: 8001–8014.
10.1093/nar/gkq698
CASPubMedWeb of Science®Google Scholar
94Bonnal S, Martinez C, Forch P, Bachi A, Wilm M, Valcarcel J. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell 2008, 32: 81–95.
10.1016/j.molcel.2008.08.008
CASPubMedWeb of Science®Google Scholar
95Seol DW, Billiar TR. A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis. J Biol Chem 1999, 274: 2072–2076.
10.1074/jbc.274.4.2072
CASPubMedWeb of Science®Google Scholar
96Srinivasula SM, Ahmad M, Guo Y, Zhan Y, Lazebnik Y, Fernandes-Alnemri T, Alnemri ES. Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. Cancer Res 1999, 59: 999–1002.

CASPubMedWeb of Science®Google Scholar
97Shultz JC, Goehe RW, Murudkar CS, Wijesinghe DS, Mayton EK, Massiello A, Hawkins AJ, Mukerjee P, Pinkerman RL, Park MA, 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. Mol Cancer Res 2011, 9: 889–900.
10.1158/1541-7786.MCR-11-0061
CASPubMedWeb of Science®Google Scholar
98Goehe RW, Shultz JC, Murudkar C, Usanovic S, Lamour NF, Massey DH, Zhang L, Camidge DR, Shay JW, Minna JD, et al. hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing. J Clin Invest 2010, 120: 3923–3939.
10.1172/JCI43552
CASPubMedWeb of Science®Google Scholar
99Shultz JC, Goehe RW, Wijesinghe DS, Murudkar C, Hawkins AJ, Shay JW, Minna JD, Chalfant CE. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res 2010, 70: 9185–9196.
10.1158/0008-5472.CAN-10-1545
CASPubMedWeb of Science®Google Scholar
100Bouillet P, Strasser A. BH3-only proteins - evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 2002, 115: 1567–1574.
10.1242/jcs.115.8.1567
CASPubMedWeb of Science®Google Scholar
101Akgul C, Moulding DA, Edwards SW. Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications. Cell Mol Life Sci 2004, 61: 2189–2199.
10.1007/s00018-004-4001-7
CASPubMedWeb of Science®Google Scholar
102Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 2002, 99: 4070–4078.
10.1182/blood.V99.11.4070
CASPubMedWeb of Science®Google Scholar
103Sun A, Tang J, Hong Y, Song J, Terranova PF, Thrasher JB, Svojanovsky S, Wang HG, Li B. Androgen receptor-dependent regulation of Bcl-xL expression: implication in prostate cancer progression. Prostate 2008, 68: 453–461.
10.1002/pros.20723
CASPubMedWeb of Science®Google Scholar
104Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H. Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology 2001, 34: 55–61.
10.1053/jhep.2001.25387
CASPubMedWeb of Science®Google Scholar
105Miller MA, Karacay B, Zhu X, O'Dorisio MS, Sandler AD. Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma. Apoptosis 2006, 11: 15–24.
10.1007/s10495-005-3258-0
CASPubMedWeb of Science®Google Scholar
106Mohr A, Zwacka RM, Jarmy G, Buneker C, Schrezenmeier H, Dohner K, Beltinger C, Wiesneth M, Debatin KM, Stahnke K. Caspase-8L expression protects CD34+ hematopoietic progenitor cells and leukemic cells from CD95-mediated apoptosis. Oncogene 2005, 24: 2421–2429.
10.1038/sj.onc.1208432
CASPubMedWeb of Science®Google Scholar
107Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 2005, 6: 611–622.
10.1038/nrg1656
CASPubMedWeb of Science®Google Scholar
108Nakamura TM, Cech TR. Reversing time: origin of telomerase. Cell 1998, 92: 587–590.
10.1016/S0092-8674(00)81123-X
CASPubMedWeb of Science®Google Scholar
109Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science 1994, 266: 2011–2015.
10.1126/science.7605428
CASPubMedWeb of Science®Google Scholar
110Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 1997, 33: 787–791.
10.1016/S0959-8049(97)00062-2
CASPubMedWeb of Science®Google Scholar
111Kilian A, Bowtell DD, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 1997, 6: 2011–2019.
10.1093/hmg/6.12.2011
CASPubMedWeb of Science®Google Scholar
112Hisatomi H, Ohyashiki K, Ohyashiki JH, Nagao K, Kanamaru T, Hirata H, Hibi N, Tsukada Y. Expression profile of a γ-deletion variant of the human telomerase reverse transcriptase gene. Neoplasia 2003, 5: 193–197.
10.1016/S1476-5586(03)80051-9
CASPubMedWeb of Science®Google Scholar
113Wang Y, Kowalski J, Tsai HL, Marik R, Prasad N, Somervell H, Lo PK, Sangenario LE, Dyrskjot L, Orntoft TF, et al. Differentiating alternative splice variant patterns of human telomerase reverse transcriptase in thyroid neoplasms. Thyroid 2008, 18: 1055–1063.
10.1089/thy.2008.0101
CASPubMedWeb of Science®Google Scholar
114Liu Y, Wu BQ, Zhong HH, Tian XX, Fang WG. Quantification of alternative splicing variants of human telomerase reverse transcriptase and correlations with telomerase activity in lung cancer. PLoS One 2012, 7: e38868.
10.1371/journal.pone.0038868
CASPubMedWeb of Science®Google Scholar
115Saeboe-Larssen S, Fossberg E, Gaudernack G. Characterization of novel alternative splicing sites in human telomerase reverse transcriptase (hTERT): analysis of expression and mutual correlation in mRNA isoforms from normal and tumour tissues. BMC Mol Biol 2006, 7: 26.
10.1186/1471-2199-7-26
CASPubMedWeb of Science®Google Scholar
116Colgin LM, Wilkinson C, Englezou A, Kilian A, Robinson MO, Reddel RR. The hTERTα splice variant is a dominant negative inhibitor of telomerase activity. Neoplasia 2000, 2: 426–432.
10.1038/sj.neo.7900112
CASPubMedWeb of Science®Google Scholar
117Huang L, Wilkinson MF. Regulation of nonsense-mediated mRNA decay. WIREs RNA 2012, 3: 807–828.
10.1002/wrna.1137
CASPubMedWeb of Science®Google Scholar
118Wong MS, Chen L, Foster C, Kainthla R, Shay JW, Wright WE. Regulation of telomerase alternative splicing: a target for chemotherapy. Cell Rep 2013, 3: 1028–1035.
10.1016/j.celrep.2013.03.011
CASPubMedWeb of Science®Google Scholar
119Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86: 353–364.
10.1016/S0092-8674(00)80108-7
CASPubMedWeb of Science®Google Scholar
120Biselli-Chicote PM, Oliveira AR, Pavarino EC, Goloni-Bertollo EM. VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in cancer. J Cancer Res Clin Oncol 2012, 138: 363–370.
10.1007/s00432-011-1073-2
CASPubMedWeb of Science®Google Scholar
121Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 2008, 8: 880–887.
10.1038/nrc2505
CASPubMedWeb of Science®Google Scholar
122Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991, 5: 1806–1814.
10.1210/mend-5-12-1806
CASPubMedWeb of Science®Google Scholar
123Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 2004, 64: 7822–7835.
10.1158/0008-5472.CAN-04-0934
CASPubMedWeb of Science®Google Scholar
124Qiu Y, Bevan H, Weeraperuma S, Wratting D, Murphy D, Neal CR, Bates DO, Harper SJ. Mammary alveolar development during lactation is inhibited by the endogenous antiangiogenic growth factor isoform, VEGF165b. FASEB J 2008, 22: 1104–1112.
10.1096/fj.07-9718com
CASPubMedWeb of Science®Google Scholar
125Cebe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A, Manlius C, Wood J, Ballmer-Hofer K. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci 2006, 63: 2067–2077.
10.1007/s00018-006-6254-9
CASPubMedWeb of Science®Google Scholar
126Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 2008, 121: 3487–3495.
10.1242/jcs.016410
CASPubMedWeb of Science®Google Scholar
127Nowak DG, Amin EM, Rennel ES, Hoareau-Aveilla C, Gammons M, Damodoran G, Hagiwara M, Harper SJ, Woolard J, Ladomery MR, et al. Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 2010, 285: 5532–5540.
10.1074/jbc.M109.074930
CASPubMedWeb of Science®Google Scholar
128Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah-Zadeh M, Welsh GI, Cheung MK, Ni L, Kase S, Rennel ES, et al. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 2011, 20: 768–780.
10.1016/j.ccr.2011.10.016
CASPubMedWeb of Science®Google Scholar
129Varey AH, Rennel ES, Qiu Y, Bevan HS, Perrin RM, Raffy S, Dixon AR, Paraskeva C, Zaccheo O, Hassan AB, et al. VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 2008, 98: 1366–1379.
10.1038/sj.bjc.6604308
CASPubMedWeb of Science®Google Scholar
130Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 2010, 70: 5649–5669.
10.1158/0008-5472.CAN-10-1040
CASPubMedWeb of Science®Google Scholar
131Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139: 871–890.
10.1016/j.cell.2009.11.007
CASPubMedWeb of Science®Google Scholar
132Monteiro J, Fodde R. Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer 2010, 46: 1198–1203.
10.1016/j.ejca.2010.02.030
CASPubMedWeb of Science®Google Scholar
133Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res 2012, 72: 4883–4889.
10.1158/0008-5472.CAN-12-1223
CASPubMedWeb of Science®Google Scholar
134Wang Y, Zhou BP. Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer 2011, 30: 603–611.
10.5732/cjc.011.10226
CASPubMedGoogle Scholar
135Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, Cheng C. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 2011, 121: 1064–1074.
10.1172/JCI44540
CASPubMedWeb of Science®Google Scholar
136Reinke LM, Xu Y, Cheng C. Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J Biol Chem 2012, 287: 36435–36442.
10.1074/jbc.M112.397125
CASPubMedWeb of Science®Google Scholar
137Shapiro IM, Cheng AW, Flytzanis NC, Balsamo M, Condeelis JS, Oktay MH, Burge CB, Gertler FB. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 2011, 7: e1002218.
10.1371/journal.pgen.1002218
CASPubMedWeb of Science®Google Scholar
138Warburg O. On the origin of cancer cells. Science 1956, 123: 309–314.
10.1126/science.123.3191.309
CASPubMedWeb of Science®Google Scholar
139Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324: 1029–1033.
10.1126/science.1160809
CASPubMedWeb of Science®Google Scholar
140Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 2009, 23: 537–548.
10.1101/gad.1756509
CASPubMedWeb of Science®Google Scholar
141Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008, 452: 230–233.
10.1038/nature06734
CASPubMedWeb of Science®Google Scholar
142David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010, 463: 364–368.
10.1038/nature08697
CASPubMedWeb of Science®Google Scholar
143Noguchi 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.
10.1016/S0021-9258(18)67091-7
CASPubMedWeb of Science®Google Scholar
144Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A 2010, 107: 1894–1899.
10.1073/pnas.0914845107
CASPubMedWeb of Science®Google Scholar
145Ferguson EC, Rathmell JC. New roles for pyruvate kinase M2: working out the Warburg effect. Trends Biochem Sci 2008, 33: 359–362.
10.1016/j.tibs.2008.05.006
CASPubMedWeb of Science®Google Scholar
146Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 2011, 43: 969–980.
10.1016/j.biocel.2010.02.005
CASPubMedWeb of Science®Google Scholar
147Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 1998, 6: 195–210.
10.1016/S0969-2126(98)00021-5
CASPubMedWeb of Science®Google Scholar
148Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010, 329: 1492–1499.
10.1126/science.1188015
CASPubMedWeb of Science®Google Scholar
149Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007, 117: 1137–1146.
10.1172/JCI31405
CASPubMedWeb of Science®Google Scholar
150Yang L, Pang Y, Moses HL. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 2010, 31: 220–227.
10.1016/j.it.2010.04.002
CASPubMedWeb of Science®Google Scholar
151Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res 2010, 107: 57–117.
10.1016/S0065-230X(10)07003-X
CASPubMedWeb of Science®Google Scholar
152Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009, 182: 4499–4506.
10.4049/jimmunol.0802740
CASPubMedWeb of Science®Google Scholar
153Trowbridge IS, Thomas ML. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu Rev Immunol 1994, 12: 85–116.
10.1146/annurev.iy.12.040194.000505
CASPubMedWeb of Science®Google Scholar
154Mustelin T, Rahmouni S, Bottini N, Alonso A. Role of protein tyrosine phosphatases in T cell activation. Immunol Rev 2003, 191: 139–147.
10.1034/j.1600-065X.2003.00014.x
CASPubMedWeb of Science®Google Scholar
155Majeti R, Bilwes AM, Noel JP, Hunter T, Weiss A. Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 1998, 279: 88–91.
10.1126/science.279.5347.88
CASPubMedWeb of Science®Google Scholar
156Hermiston ML, Xu Z, Majeti R, Weiss A. Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. J Clin Invest 2002, 109: 9–14.
10.1172/JCI0214794
CASPubMedWeb of Science®Google Scholar
157Lynch KW. Consequences of regulated pre-mRNA splicing in the immune system. Nat Rev Immunol 2004, 4: 931–940.
10.1038/nri1497
CASPubMedWeb of Science®Google Scholar
158Xu Z, Weiss A. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat Immunol 2002, 3: 764–771.
10.1038/ni822
CASPubMedWeb of Science®Google Scholar
159Chiou NT, Shankarling G, Lynch KW. HnRNP L and HnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly. Mol Cell 2013, 49: 972–982.
10.1016/j.molcel.2012.12.025
CASPubMedWeb of Science®Google Scholar
160Rothrock CR, House AE, Lynch KW. HnRNP L represses exon splicing via a regulated exonic splicing silencer. EMBO J 2005, 24: 2792–2802.
10.1038/sj.emboj.7600745
CASPubMedWeb of Science®Google Scholar
161Heyd F, Lynch KW. Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Mol Cell 2010, 40: 126–137.
10.1016/j.molcel.2010.09.013
CASPubMedWeb of Science®Google Scholar
162Oberdoerffer S, Moita LF, Neems D, Freitas RP, Hacohen N, Rao A. Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL. Science 2008, 321: 686–691.
10.1126/science.1157610
CASPubMedWeb of Science®Google Scholar
163Topp JD, Jackson J, Melton AA, Lynch KW. A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA 2008, 14: 2038–2049.
10.1261/rna.1212008
CASPubMedWeb of Science®Google Scholar
164Wu Z, Jia X, de la Cruz L, Su XC, Marzolf B, Troisch P, Zak D, Hamilton A, Whittle B, Yu D, et al. Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL. Immunity 2008, 29: 863–875.
10.1016/j.immuni.2008.11.004
CASPubMedWeb of Science®Google Scholar
165Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, Oberdoerffer P, Sandberg R, Oberdoerffer S. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011, 479: 74–79.
10.1038/nature10442
CASPubMedWeb of Science®Google Scholar
166Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012, 21: 822–835.
10.1016/j.ccr.2012.04.025
CASPubMedWeb of Science®Google Scholar
167Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012, 148: 349–361.
10.1016/j.cell.2011.11.025
CASPubMedWeb of Science®Google Scholar
168Lenos K, Grawenda AM, Lodder K, Kuijjer ML, Teunisse AF, Repapi E, Grochola LF, Bartel F, Hogendoorn PC, Wuerl P, et al. Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. Cancer Res 2012, 72: 4074–4084.
10.1158/0008-5472.CAN-12-0215
CASPubMedWeb of Science®Google Scholar
169Onel K, Cordon-Cardo C. MDM2 and prognosis. Mol Cancer Res 2004, 2: 1–8.
10.1158/1541-7786.1.2.1
CASPubMedWeb of Science®Google Scholar
170Prodosmo A, Giglio S, Moretti S, Mancini F, Barbi F, Avenia N, Di Conza G, Schunemann HJ, Pistola L, Ludovini V, et al. Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. J Mol Med (Berl) 2008, 86: 585–596.
10.1007/s00109-008-0322-6
CASPubMedWeb of Science®Google Scholar
171Bonnal S, Vigevani L, Valcarcel J. The spliceosome as a target of novel antitumour drugs. Nat Rev Drug Discov 2012, 11: 847–859.
10.1038/nrd3823
CASPubMedWeb of Science®Google Scholar
172Miura K, Fujibuchi W, Unno M. Splice isoforms as therapeutic targets for colorectal cancer. Carcinogenesis 2012, 33: 2311–2319.
10.1093/carcin/bgs347
CASPubMedWeb of Science®Google Scholar
173Rennel ES, Harper SJ, Bates DO. Therapeutic potential of manipulating VEGF splice isoforms in oncology. Future Oncol 2009, 5: 703–712.
10.2217/fon.09.33
CASPubMedWeb of Science®Google Scholar
174Narla G, Difeo A, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, Katz A, Isaacs WB, Hebbring S, Komiya A, et al. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 2005, 65: 1213–1222.
10.1158/0008-5472.CAN-04-4249
CASPubMedWeb of Science®Google Scholar
175Narla G, DiFeo A, Fernandez Y, Dhanasekaran S, Huang F, Sangodkar J, Hod E, Leake D, Friedman SL, Hall SJ, et al. KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis. J Clin Invest 2008, 118: 2711–2721.
10.1172/JCI34780
CASPubMedWeb of Science®Google Scholar
176Hatami R, Sieuwerts AM, Izadmehr S, Yao Z, Qiao RF, Papa L, Look MP, Smid M, Ohlssen J, Levine AC, et al. KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci Transl Med 2013, 5: 169ra112.
10.1126/scitranslmed.3004688
CASWeb of Science®Google Scholar
177Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 2000, 14: 927–939.
10.1101/gad.14.8.927
CASPubMedWeb of Science®Google Scholar
178Orban TI, Olah E. Emerging roles of BRCA1 alternative splicing. Mol Pathol 2003, 56: 191–197.
10.1136/mp.56.4.191
CASPubMedWeb of Science®Google Scholar
179Liu HX, Cartegni L, Zhang MQ, Krainer AR. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet 2001, 27: 55–58.
10.1038/83762
CASPubMedWeb of Science®Google Scholar
180Mazoyer S, Puget N, Perrin-Vidoz L, Lynch HT, Serova-Sinilnikova OM, Lenoir GM. A BRCA1 nonsense mutation causes exon skipping. Am J Hum Genet 1998, 62: 713–715.
10.1086/301768
CASPubMedWeb of Science®Google Scholar
181Goina E, Skoko N, Pagani F. Binding of DAZAP1 and hnRNPA1/A2 to an exonic splicing silencer in a natural BRCA1 exon 18 mutant. Mol Cell Biol 2008, 28: 3850–3860.
10.1128/MCB.02253-07
CASPubMedWeb of Science®Google Scholar
182Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol 2004, 11: 512–518.
10.1038/nsmb775
CASPubMedWeb of Science®Google Scholar
183Huyton T, Bates PA, Zhang X, Sternberg MJ, Freemont PS. The BRCA1 C-terminal domain: structure and function. Mutat Res 2000, 460: 319–332.
10.1016/S0921-8777(00)00034-3
CASPubMedWeb of Science®Google Scholar
184Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011, 478: 64–69.
10.1038/nature10496
CASPubMedWeb of Science®Google Scholar
185Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L, Ramsay AJ, Bea S, Pinyol M, Martinez-Trillos A, et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2012, 44: 47–52.
10.1038/ng.1032
CASWeb of Science®Google Scholar
186Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, Pellagatti A, Wainscoat JS, Hellstrom-Lindberg E, Gambacorti-Passerini C, et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 2011, 365: 1384–1395.
10.1056/NEJMoa1103283
CASPubMedWeb of Science®Google Scholar
187Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011, 365: 2497–2506.
10.1056/NEJMoa1109016
CASPubMedWeb of Science®Google Scholar
188Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, Przychodzen B, Bupathi M, Guinta K, Afable MG, et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012, 119: 3203–3210.
10.1182/blood-2011-12-399774
CASPubMedWeb of Science®Google Scholar
189Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, et al. A landscape of driver mutations in melanoma. Cell 2012, 150: 251–263.
10.1016/j.cell.2012.06.024
CASPubMedWeb of Science®Google Scholar
190Horiguchi K, Sakamoto K, Koinuma D, Semba K, Inoue A, Inoue S, Fujii H, Yamaguchi A, Miyazawa K, Miyazono K, et al. TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP. Oncogene 2012, 31: 3190–3201.
10.1038/onc.2011.493
CASPubMedWeb of Science®Google Scholar
191Sureau A, Gattoni R, Dooghe Y, Stevenin J, Soret J. SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J 2001, 20: 1785–1796.
10.1093/emboj/20.7.1785
CASPubMedWeb of Science®Google Scholar
192Wollerton MC, Gooding C, Wagner EJ, Garcia-Blanco MA, Smith CW. Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay. Mol Cell 2004, 13: 91–100.
10.1016/S1097-2765(03)00502-1
CASPubMedWeb of Science®Google Scholar
193Lareau LF, Inada M, Green RE, Wengrod JC, Brenner SE. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 2007, 446: 926–929.
10.1038/nature05676
CASPubMedWeb of Science®Google Scholar
194Ni JZ, Grate L, Donohue JP, Preston C, Nobida N, O'Brien G, Shiue L, Clark TA, Blume JE, Ares M Jr. Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev 2007, 21: 708–718.
10.1101/gad.1525507
CASPubMedWeb of Science®Google Scholar
195Sun S, Zhang Z, Sinha R, Karni R, Krainer AR. SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control. Nat Struct Mol Biol 2010, 17: 306–312.
10.1038/nsmb.1750
CASPubMedWeb of Science®Google Scholar
196Anczukow O, Rosenberg AZ, Akerman M, Das S, Zhan L, Karni R, Muthuswamy SK, Krainer AR. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 2012, 19: 220–228.
10.1038/nsmb.2207
CASPubMedWeb of Science®Google Scholar
197Das S, Anczukow O, Akerman M, Krainer AR. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep 2012, 1: 110–117.
10.1016/j.celrep.2011.12.001
CASPubMedWeb of Science®Google Scholar
198Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007, 14: 185–193.
10.1038/nsmb1209
CASPubMedWeb of Science®Google Scholar
199Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci U S A 2008, 105: 15323–15327.
10.1073/pnas.0801376105
CASPubMedWeb of Science®Google Scholar
200Xiao SH, Manley JL. Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO J 1998, 17: 6359–6367.
10.1093/emboj/17.21.6359
CASPubMedWeb of Science®Google Scholar
201Gui JF, Lane WS, Fu XD. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature 1994, 369: 678–682.
10.1038/369678a0
CASPubMedWeb of Science®Google Scholar
202Ghigna C, Valacca C, Biamonti G. Alternative splicing and tumor progression. Curr Genomics 2008, 9: 556–570.
10.2174/138920208786847971
CASPubMedWeb of Science®Google Scholar
203Heyd F, Lynch KW. Degrade, move, regroup: signaling control of splicing proteins. Trends Biochem Sci 2011, 36: 397–404.
10.1016/j.tibs.2011.04.003
CASPubMedWeb of Science®Google Scholar
204Zhou Z, Qiu J, Liu W, Zhou Y, Plocinik RM, Li H, Hu Q, Ghosh G, Adams JA, Rosenfeld MG, et al. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol Cell 2012, 47: 422–433.
10.1016/j.molcel.2012.05.014
CASPubMedWeb of Science®Google Scholar
205Blaustein M, Pelisch F, Tanos T, Munoz MJ, Wengier D, Quadrana L, Sanford JR, Muschietti JP, Kornblihtt AR, Caceres JF, et al. Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nat Struct Mol Biol 2005, 12: 1037–1044.
10.1038/nsmb1020
CASPubMedWeb of Science®Google Scholar
206Blaustein M, Pelisch F, Coso OA, Bissell MJ, Kornblihtt AR, Srebrow A. Mammary epithelial-mesenchymal interaction regulates fibronectin alternative splicing via phosphatidylinositol 3-kinase. J Biol Chem 2004, 279: 21029–21037.
10.1074/jbc.M314260200
CASPubMedWeb of Science®Google Scholar
207Sinha R, Allemand E, Zhang Z, Karni R, Myers MP, Krainer AR. Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF. Mol Cell Biol 2010, 30: 2762–2774.
10.1128/MCB.01270-09
CASPubMedWeb of Science®Google Scholar
208Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI. Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol Cell Proteomics 2006, 5: 2298–2310.
10.1074/mcp.M600212-MCP200
CASPubMedWeb of Science®Google Scholar
209Vethantham V, Rao N, Manley JL. Sumoylation modulates the assembly and activity of the pre-mRNA 3′ processing complex. Mol Cell Biol 2007, 27: 8848–8858.
10.1128/MCB.01186-07
CASPubMedWeb of Science®Google Scholar
210Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009, 136: 215–233.
10.1016/j.cell.2009.01.002
CASPubMedWeb of Science®Google Scholar
211Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008, 9: 102–114.
10.1038/nrg2290
CASPubMedWeb of Science®Google Scholar
212Engels BM, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene 2006, 25: 6163–6169.
10.1038/sj.onc.1209909
CASPubMedWeb of Science®Google Scholar
213Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 2006, 20: 515–524.
10.1101/gad.1399806
CASPubMedWeb of Science®Google Scholar
214Boutz PL, Chawla G, Stoilov P, Black DL. MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development. Genes Dev 2007, 21: 71–84.
10.1101/gad.1500707
CASPubMedWeb of Science®Google Scholar
215Yoshino H, Enokida H, Chiyomaru T, Tatarano S, Hidaka H, Yamasaki T, Gotannda T, Tachiwada T, Nohata N, Yamane T, et al. Tumor suppressive microRNA-1 mediated novel apoptosis pathways through direct inhibition of splicing factor serine/arginine-rich 9 (SRSF9/SRp30c) in bladder cancer. Biochem Biophys Res Commun 2012, 417: 588–593.
10.1016/j.bbrc.2011.12.011
CASPubMedWeb of Science®Google Scholar
216Montes M, Cloutier A, Sanchez-Hernandez N, Michelle L, Lemieux B, Blanchette M, Hernandez-Munain C, Chabot B, Sune C. TCERG1 regulates alternative splicing of the Bcl-x gene by modulating the rate of RNA polymerase II transcription. Mol Cell Biol 2012, 32: 751–762.
10.1128/MCB.06255-11
CASPubMedWeb of Science®Google Scholar
217Nogues G, Kadener S, Cramer P, de la Mata M, Fededa JP, Blaustein M, Srebrow A, Kornblihtt AR. Control of alternative pre-mRNA splicing by RNA Pol II elongation: faster is not always better. IUBMB Life 2003, 55: 235–241.
10.1080/1521654031000119830
CASPubMedWeb of Science®Google Scholar
218Nogues G, Munoz MJ, Kornblihtt AR. Influence of polymerase II processivity on alternative splicing depends on splice site strength. J Biol Chem 2003, 278: 52166–52171.
10.1074/jbc.M309156200
CASPubMedWeb of Science®Google Scholar
219Close P, East P, Dirac-Svejstrup AB, Hartmann H, Heron M, Maslen S, Chariot A, Soding J, Skehel M, Svejstrup JQ. DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation. Nature 2012, 484: 386–389.
10.1038/nature10925
CASPubMedWeb of Science®Google Scholar
220Roberts GC, Gooding C, Mak HY, Proudfoot NJ, Smith CW. Co-transcriptional commitment to alternative splice site selection. Nucleic Acids Res 1998, 26: 5568–5572.
10.1093/nar/26.24.5568
CASPubMedWeb of Science®Google Scholar
221Ip JY, Schmidt D, Pan Q, Ramani AK, Fraser AG, Odom DT, Blencowe BJ. Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res 2011, 21: 390–401.
10.1101/gr.111070.110
CASPubMedWeb of Science®Google Scholar
222Kornblihtt AR, Schor IE, Allo M, Dujardin G, Petrillo E, Munoz MJ. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol 2013, 14: 153–165.
10.1038/nrm3525
CASPubMedWeb of Science®Google Scholar
223Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ. Dynamic integration of splicing within gene regulatory pathways. Cell 2013, 152: 1252–1269.
10.1016/j.cell.2013.02.034
CASPubMedWeb of Science®Google Scholar
224Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T. Epigenetics in alternative pre-mRNA splicing. Cell 2011, 144: 16–26.
10.1016/j.cell.2010.11.056
CASPubMedWeb of Science®Google Scholar
225Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. Regulation of alternative splicing by histone modifications. Science 2010, 327: 996–1000.
10.1126/science.1184208
CASPubMedWeb of Science®Google Scholar
226de la Mata M, Alonso CR, Kadener S, Fededa JP, Blaustein M, Pelisch F, Cramer P, Bentley D, Kornblihtt AR. A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell 2003, 12: 525–532.
10.1016/j.molcel.2003.08.001
PubMedWeb of Science®Google Scholar

Citing Literature

Volume4, Issue5

September/October 2013

Pages 547-566

WIREs RNA

Alternative RNA splicing and cancer

Abstract

REFERENCES

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

WIREs RNA

Alternative RNA splicing and cancer

Abstract

REFERENCES

Citing Literature

References

Related

Information