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The Scientific World Journal
Volume 2013 (2013), Article ID 703568, 8 pages
http://dx.doi.org/10.1155/2013/703568
Review Article

Alternative Splicing for Diseases, Cancers, Drugs, and Databases

1Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
2Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
3Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan
7Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 300, Taiwan
8Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 807, Taiwan
9Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
10Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Received 1 April 2013; Accepted 30 April 2013

Academic Editors: F. Alvarez-Valin and A. Komiya

Copyright © 2013 Jen-Yang Tang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Alternative splicing is a major diversification mechanism in the human transcriptome and proteome. Several diseases, including cancers, have been associated with dysregulation of alternative splicing. Thus, correcting alternative splicing may restore normal cell physiology in patients with these diseases. This paper summarizes several alternative splicing-related diseases, including cancers and their target genes. Since new cancer drugs often target spliceosomes, several clinical drugs and natural products or their synthesized derivatives were analyzed to determine their effects on alternative splicing. Other agents known to have modulating effects on alternative splicing during therapeutic treatment of cancer are also discussed. Several commonly used bioinformatics resources are also summarized.

1. Introduction to Alternative Splicing

Alternative splicing of RNA is a key mechanism of increasing complexity in mRNA and proteins [1]. Since alternative splicing apparently controls almost all human gene activities, imbalances in the this splicing process may affect the progression of various human diseases and cancers [2]. Varying alternations in excision and/or inclusion of exons may generate different mRNA transcripts and corresponding proteins. Therefore, in addition to mediating changes in protein structure, function, and localization [3], alternative splicing in higher eukaryotes affects the differentiation and development of cancer and other diseases [4].

2. Alternative Splicing and Diseases

Alternative RNA splicing is commonly reported in neurological and muscle diseases [57]. Studies show that these diseases at least partly result from alternative splicing, which regulates the complexity of integral membrane proteins, including changes in their topology, solubility, and signal peptides [3]. For example, aberrant alternative splicing has shown associations with Parkinson disease [3, 8]. For spinal muscular atrophy (SMA), the level of survival motor neuron (SMN) protein was downregulated by its alternative splicing [9]. Therapies for SMA have recently improved by targeting RNA splicing for inclusion of exon 7 into SMN mRNA [10]. Phorbol 12-myristate 13-acetate was reported to modulate the alternative splicing of sarcoplasmic reticulum -ATPase1 (SERCA1) which is dysregulated in myotonic dystrophy type 1 disease [11].

Additionally, alternative splicing reportedly regulates heart development [12], cardiovascular disease [13], blood coagulation [14], cholesterol homeostasis [15], cellular proliferation, apoptosis, immunity [16], and systemic sclerosis [17]. For example, heart-specific knockout of the serine/arginine- (SR-) rich family of splicing factors, ASF/SF2, produces cardiomyopathy and affects splicing of cardiac troponin T and LIM domain-binding protein [18]. Specific CLK inhibitors (dichloroindolyl enaminonitrile KH-CB19) of CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4) can inhibit phosphorylation of cellular SR splicing factors and affect the splicing of tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF) [19].

Using exon array, the global mRNA splicing profile of ischemic cardiomyopathy has been investigated, and the alternative splicing of four main sarcomere genes, such as cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C, gamma (FLNC), was dysregulated [20]. The alternative splicing of blood coagulation-related genes including tissue factor (coagulation factor III), tissue factor pathway inhibitor (TFPI), and coagulation factor XI has been well reviewed [14]. For cholesterol production and uptake, alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR) can suppress their protein activities [21, 22]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) [23], HMG-CoA synthase (HMGCS1) [24], and mevalonate kinase [25] also reported to be involved in cholesterol biosynthesis and receptor-mediated uptake through alternative splicing.

3. Alternative Splicing and Cancer

In cancer-associated genes, splicing has important roles in oncogenesis, tumor suppression [26], and metastasis [27]. Alterations in alternative splicing are commonly reported in various cancers [2729]. Reported examples include p53 and PTEN [30], kallikrein-related peptidase 12 (KLK12) [31], breast cancer early-onset 1 (BRCA1) [32], protein N-arginine methyltransferases 2 (PRMT2) [33], and CDC25 phosphatases [34] in breast cancer; lysyl oxidase-like 4 (LOXL4) [35] and growth factor receptor-bound protein 7 (GRB7) in ovarian cancer [36]; androgen receptor in prostate cancer [37]; tissue inhibitor of metalloproteinases-1 (TIMP1) and the cell adhesion molecule CD44 in colon cancer [38, 39]; Bcl-xL, CD44, and others in lung cancer [40]; calpain 3 in melanoma [41]; and Krüppel-like factor 6 (KLF6) in liver cancer [42]. Therefore, alternative spliced variants are potential biomarkers [43, 44] for the cancer diagnosis/prognosis and may be the targets for cancer therapy based on specific splicing correction treatments.

Single nucleotide polymorphisms (SNPs) affecting exon skipping has reviewed to confer to complex diseases [45]. The improvement of high-throughput technologies such as RNA-Seq [46, 47] and exon arrays [48, 49] is helpful to identify the genome-wide cancer-associated splicing variants. Splicing changes may associate with lung and prostate cancer risk in terms of some SNPs. For example, a coding synonymous SNP G870A of cyclin D1 (CCND1) with a modulating ability to its splice pattern was reported to be associated with lung cancer susceptibility [50]. Similarly, some coding synonymous SNPs may generate new splicing sites in the middle of an exon of p53 gene to change splicing [51]. Mutations in the adenomatous polyposis coli (APC) [52] and BRCA1 [53, 54] genes have reported to skip exon by altering splicing. Furthermore, an intronic SNP, IVS −27 G A/IVS A, creates a new splicing factor SR-binding site and deletes two other overlapping SR-binding sites, generating three alternative splicing forms of KLF6 (KLF6 SV1-3) [55]. This SNP was found to be associated with prostate cancer [56]. For lung cancer study, the tumor patients with overexpression of KLF6 SV1 have lower survival [56, 57].

Actually, the information of many SNPs located in 3′ and 5′ splicing sites is searchable in the dbSNP in NCBI website (http://www.ncbi.nlm.nih.gov/snp) when the “limit” function is chosen. Researchers may choose the SNPs of splicing sites located in interested genes to identify their association relationships to diseases and cancers. A database consisting of genome-wide SNP and splicing sites, namely, ssSNPTarget [58] was designed to search the splice site SNPs (ssSNPs) by input of gene symbol, SNP rs number, transcript ID, or genomic position (http://variome.kobic.re.kr/ssSNPTarget/).

4. Alternative Splicing-Related Drugs and Natural Products

Splice modulating therapies have been developed for human disease [5961] and cancer therapy [62, 63]. Antitumor drugs have been developed to target alternative splicing [64], splice variants [65], and spliceosomes [66, 67]. For example, pharmacological interventions may be affected by mRNA transcript diversity [68]. To correct aberrant splicing, specific mRNA transcripts have been targeted in genetic disorders such as Duchenne muscular dystrophy. Since mutations of splicing factor 3B subunit 1 (SF3B1) are common in several haematological malignancies, the use of various natural products and their synthetic derivatives in therapies targeting SF3B has proven highly effective [67].

For drug discovery for SMA, several small molecules including sodium vanadate [69], aclarubicin [70], and indoprofen [71], hydroxyurea [72], valproate [73], 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) [74], and phenylbutyrate [75] that increases inclusion of exon 7 of SMN2 gene have been identified, although some of them may have side effects. Recently, novel phosphatase modulators, namely, pseudocantharidins have been discovered with the similar regulating function to SMN splicing [76]. Valproic acid was found to enhance SMN2 expression in SMA cell model involving the SF2/ASF and hnRNPA1 [77].

Clinical drugs such as novantrone (mitoxantrone) can enhance the effectiveness of therapeutic treatments for familial neurodegenerative diseases by stabilizing the tau pre-mRNA splicing regulatory element [78]. Tamoxifen has proven effective for clinical treatment of estrogen receptor- (ER-) positive breast cancer [79]. In endometrial cancer cells, alternative splicing of ER involving ER-alpha36 is also known to enhance the agonist activity of tamoxifen [80].

Natural products, including many xenobiotics, are also known to impair alternative splicing [81]. For example, natural products such as pladienolide B and FR901464 [82, 83] are known to affect spliceosome function. However, the synthesis of these compounds is complicated by their multiple stereocenters. A recent study synthesized Sudemycins, which are novel analogues of FR901464. By inducing alternative gene splicing, the Sudemycins conferred both in vitro and in vivo antitumor effects [84]. Alternative splicing has also shown regulating effects on the antitumor drug Spliceostatin A, a stabilized derivative of a Pseudomonas bacterial fermentation product [85] which specifically targets the SF3b spliceosome subcomplex to inhibit pre-mRNA splicing [86]. Meayamycin, an analogue of the natural antitumor product FR901464 [87], inhibits RNA splicing against multidrug-resistant cells and performs antiproliferative effect against human breast cancer MCF-7 cells by suppression of alternative splicing [88]. These results suggest that, because of their modulating effects on RNA splicing, xenobiotic analogs have potential use as chemical probes and as anticancer agents. Similarly, the polyketide natural product borrelidin inhibits cancer metastasis by modulating alternative splicing in VEGF [89]. Antitumor effects involving alternative splicing [90, 91] have also been reported in natural dietary products. For example, resveratrol can modulate exon inclusion of SRp20 and SMN2 pre-mRNAs and induce the expression of processing factors of alternative splicing such as ASF/SF2, hnRNPA1, and HuR [92].

Recent studies have investigated the role of splice variants in apoptotic pathways [93, 94]. Regulation of alternative splicing genes may have anticancer effects. For example, BCL-Xs and BCL-XL have been associated with proapoptotic and antiapoptotic effects, respectively, during the progression of cancer [67, 95, 96]. The ratio of BCL-Xs/BCL-XL can be decreased by the treatment of protein kinase C (PKC) inhibitor and apoptotic inducer staurosporine in 293 cells [97]. Soluble and membrane-bound forms of TNF receptor superfamily, member 6 (FAS) containing exons 5/7 and 5/6/7 also display proapoptotic and antiapoptotic effects, respectively [67]. The caspase 9 (CASP9) gene has two antagonistic isoforms, proapoptotic Casp9a and prosurvival Casp9b, and its splicing is dysregulated in NSCLC lung cancer cell lines [98].

Alternative splicing is regulated by chromatin structure and histone modifications [4]. In thyroid tumor cells, for example, histone deacetylase inhibitors such as butyrate modulate transcription and alternative splicing of prohibitin [99]. A study of bovine epithelial cells showed that butyrate, a major metabolite generated by bacterial fermentation of dietary fiber in colon cells, has regulating effects on apoptosis and cell proliferation through alternative splicing [100]. Since histone deacetylase inhibitor may have antitumor effects, the identification of this kind of inhibitor in natural products can improve drug development for tumor therapy.

5. Alternative Splicing-Related Bioinformatics Resources

Several bioinformatics analyses for the detection and regulation of alternative splicing have been well reviewed [101103]. However, these literatures mainly focused on the methodology for detection of alternative splicing, and the databases of alternative splicing are less addressed and summarized. Here, we collect several helpful bioinformatics resources related to alternative splicing as shown in Table 1.

tab1
Table 1: The bioinformatics resources related to alternative splicing (yrs 2001–2013)*.

For example, AsMamDB [104] is one of the early established alternative splice databases of mammals, although their websites are not functional currently. PALS db [105] provides the putative alternative splicing database based on UniGene clusters of human and mouse sources which mainly consist of EST data. Similarly, some databases such as EASED [107] and AVATAR [108] are constructed by datasets of EST and mRNAs. ASAP [106] provides the detail annotation for exon-intron boundary, alternative splicing, and its tissue specificity for the user to design probes for distinguishing different splicing isoforms. MAASE [109] is also specifically designed to apply in splicing microarray experiments. In contrast, Splicy [115] provide the web-based tool to predict possible alternative splicing events from Affymetrix probe set inputs. ASTALAVISTA [116] provides alternative splicing prediction for transcriptome data from GENCODE, REFSEQ, and ENSEMBL as well as from custom gene datasets. Furthermore, SpliceCenter [120] is a web server for predicting the influence of alternative splicing on RT-PCR, RNAi, microarray, and peptide-based data.

Both PolyA_DB [110] and AltTrans provide the information for alternative polyadenylation [111]. For AltTrans, the AltSplice pipeline on splicing and the AltPAS pipeline on polyadenylation were implemented. ASTD [126] also provides the variants for splicing, transcription initiation, and polyadenylation. Of note, the dataset of transcriptomics for alternative splicing is larger than for alternative polyadenylation. GRSDB [112] is a mammalian database of alternative splicing based on quadruplex forming G-rich sequences which modulate the 3′ end processing of pre-mRNAs.

Additionally, several comprehensive databases for alternative splicing have been developed such as HOLLYWOOD [113], ASD [114], BIPASS [117], ECgene [118], ASPicDB [121], AspAlt [125], H-DBAS [128], SPLOOCE [129], and APPRIS [130]. For example, the ECgene provides EST and serial analysis of gene expression (SAGE) data-based annotation and visualization for alternative splicing (AS). The ASPicDB provides EST-based tissue-specific splicing information of normal and cancer cells. The H-DBAS provides alternative splicing annotation based on RNA-Seq transcriptomics data. The APPRIS provides the annotation for principal isoform as the standard reference sequence for each gene.

Some resources of alternative splicing have special features such as splice signals in EuSplice [119], tandem splice sites in TassDB2 [127], mutational evidence-based analysis in Alternative Splicing Mutation Database [122], splicing proteins in SpliceAid 2 [131], and transcription factors in TFClass [132]. However, the impacts of alternative splicing on the spliced transcripts encoded protein structure are less addressed. Some databases such as ProSAS [123] and SpliVaP [124] also provide the protein isoforms from the alternative splicing effects. In ProSAS, the protein isoforms of splicing transcripts are annotated in Ensembl or SwissProt. In SpliVap, protein signatures of alternative forms are annotated in terms of Pfam domains and PRINTS fingerprints.

6. Conclusion

Accumulating evidence shows that alternative splicing can be selectively targeted in several genes of cancer cells. An exciting possibility raised by this study is that the effectiveness of anticancer therapies may be enhanced by clinical drugs, natural products, and their synthesized analogs that target alternative splicing machinery. Some alternative splicing-related databases and web servers may also helpful to improve the alternative splicing therapy for treating cancer and other diseases.

Acknowledgments

This study was supported by Grants from the National Science Council (NSC101-2320-B-037-049), the Department of Health, Executive Yuan, China (DOH102-TD-C-111-002), the Technology Development Programs, Ministry of Economic Affairs, Taiwan (102-EC-17-A-01-04-0525), the Kaohsiung Medical University Research Foundation (KMUER001), and the National Sun Yat-Sen University-KMU Joint Research Project (no. NSYSU-KMU 102-034).

References

  1. D. Brett, H. Pospisil, J. Valcárcel, J. Reich, and P. Bork, “Alternative splicing and genome complexity,” Nature Genetics, vol. 30, no. 1, pp. 29–30, 2002. View at Publisher · View at Google Scholar · View at Scopus
  2. C. Ghigna, M. De Toledo, S. Bonomi et al., “Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives,” RNA Biology, vol. 7, no. 4, pp. 495–503, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. K. F. Mittendorf, C. L. Deatherage, M. D. Ohi, and C. R. Sanders, “Tailoring of membrane proteins by alternative splicing of pre-mRNA,” Biochemistry, vol. 51, no. 28, pp. 5541–5556, 2012. View at Publisher · View at Google Scholar
  4. R. F. Luco, M. Allo, I. E. Schor, A. R. Kornblihtt, and T. Misteli, “Epigenetics in alternative pre-mRNA splicing,” Cell, vol. 144, no. 1, pp. 16–26, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. M. G. Poulos, R. Batra, K. Charizanis, and M. S. Swanson, “Developments in RNA splicing and disease,” Cold Spring Harbor Perspectives in Biology, vol. 3, no. 1, Article ID a000778, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. J. D. Mills and M. Janitz, “Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases,” Neurobiology of Aging, vol. 33, no. 5, pp. 1011–1024, 2012.
  7. K. Yap and E. V. Makeyev, “Regulation of gene expression in mammalian nervous system through alternative pre-mRNA splicing coupled with RNA quality control mechanisms,” Molecular and Cellular Neuroscience, 2013. View at Publisher · View at Google Scholar
  8. R. H. Fu, S. P. Liu, S. J. Huang et al., “Aberrant alternative splicing events in Parkinson's disease,” Cell Transplantation, vol. 22, no. 4, pp. 653–661, 2013. View at Publisher · View at Google Scholar
  9. J. Pearn, “Classification of spinal muscular atrophies,” Lancet, vol. 1, no. 8174, pp. 919–922, 1980. View at Scopus
  10. J. Zhou, X. Zheng, and H. Shen, “Targeting RNA-splicing for SMA treatment,” Molecules and Cells, vol. 33, no. 3, pp. 223–228, 2012. View at Publisher · View at Google Scholar
  11. Y. Zhao, M. Koebis, S. Suo, S. Ohno, and S. Ishiura, “Regulation of the alternative splicing of sarcoplasmic reticulum Ca2+-ATPase1 (SERCA1) by phorbol 12-myristate 13-acetate (PMA) via a PKC pathway,” Biochemical and Biophysical Research Communications, vol. 423, no. 2, pp. 212–217, 2012. View at Publisher · View at Google Scholar
  12. T. A. Cooper, “Alternative splicing regulation impacts heart development,” Cell, vol. 120, no. 1, pp. 1–2, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. E. Lara-Pezzi, A. Dopazo, and M. Manzanares, “Understanding cardiovascular disease: a journey through the genome (and what we found there),” Disease Models & Mechanisms, vol. 5, no. 4, pp. 434–443, 2012. View at Publisher · View at Google Scholar
  14. V. Y. Bogdanov, “Blood coagulation and alternative pre-mRNA splicing: an overview,” Current Molecular Medicine, vol. 6, no. 8, pp. 859–869, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. M. W. Medina and R. M. Krauss, “Alternative splicing in the regulation of cholesterol homeostasis,” Current Opinion in Lipidology, vol. 24, no. 2, pp. 147–152, 2013. View at Publisher · View at Google Scholar
  16. K. Endo-Umeda, S. Uno, K. Fujimori et al., “Differential expression and function of alternative splicing variants of human liver X receptor alpha,” Molecular Pharmacology, vol. 81, no. 6, pp. 800–810, 2012. View at Publisher · View at Google Scholar
  17. M. Manetti, S. Guiducci, L. Ibba-Manneschi, and M. Matucci-Cerinic, “Impaired angiogenesis in systemic sclerosis: the emerging role of the antiangiogenic VEGF(165)b splice variant,” Trends in Cardiovascular Medicine, vol. 21, no. 7, pp. 204–210, 2011. View at Publisher · View at Google Scholar
  18. X. Xu, D. Yang, J. H. Ding et al., “ASF/SF2-regulated CaMKIIδ alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle,” Cell, vol. 120, no. 1, pp. 59–72, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. O. Fedorov, K. Huber, A. Eisenreich et al., “Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing,” Chemistry & Biology, vol. 18, no. 1, pp. 67–76, 2011. View at Publisher · View at Google Scholar
  20. S. W. Kong, Y. W. Hu, J. W. K. Ho et al., “Heart failure-associated changes in RNA splicing of sarcomere genes,” Circulation, vol. 3, no. 2, pp. 138–146, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. R. Burkhardt, E. E. Kenny, J. K. Lowe et al., “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 2078–2084, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. H. Zhu, H. M. Tucker, K. E. Grear et al., “A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol,” Human Molecular Genetics, vol. 16, no. 14, pp. 1765–1772, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. R. J. Schmidt, Y. Zhang, Y. Zhao et al., “A novel splicing variant of proprotein convertase subtilisin/kexin type 9,” DNA and Cell Biology, vol. 27, no. 4, pp. 183–189, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. G. Gil, J. R. Smith, J. L. Goldstein, and M. S. Brown, “Optional exon in the 5′-untranslated region of 3-hydroxy-3-methylglutaryl coenzyme A synthase gene: conserved sequence and splicing pattern in humans and hamsters,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 7, pp. 1863–1866, 1987. View at Scopus
  25. S. M. Houten, J. Koster, G. J. Romeijn et al., “Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome,” European Journal of Human Genetics, vol. 9, no. 4, pp. 253–259, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. D. Kaida, T. Schneider-Poetsch, and M. Yoshida, “Splicing in oncogenesis and tumor suppression,” Cancer Science, vol. 103, no. 9, pp. 1611–1616, 2012. View at Publisher · View at Google Scholar
  27. R. M. Hagen and M. R. Ladomery, “Role of splice variants in the metastatic progression of prostate cancer,” Biochemical Society Transactions, vol. 40, no. 4, pp. 870–874, 2012. View at Publisher · View at Google Scholar
  28. J. Sampath and L. M. Pelus, “Alternative splice variants of survivin as potential targets in cancer,” Current Drug Discovery Technologies, vol. 4, no. 3, pp. 174–191, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Miura, W. Fujibuchi, and I. Sasaki, “Alternative pre-mRNA splicing in digestive tract malignancy,” Cancer Science, vol. 102, no. 2, pp. 309–316, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. N. Okumura, H. Yoshida, Y. Kitagishi, Y. Nishimura, and S. Matsuda, “Alternative splicings on p53, BRCA1 and PTEN genes involved in breast cancer,” Biochemical and Biophysical Research Communications, vol. 413, no. 3, pp. 395–399, 2011. View at Publisher · View at Google Scholar
  31. M. Talieri, M. Devetzi, A. Scorilas et al., “Human kallikrein-related peptidase 12 (KLK12) splice variants expression in breast cancer and their clinical impact,” Tumor Biology, vol. 33, no. 4, pp. 1075–1084, 2012. View at Publisher · View at Google Scholar
  32. C. Tammaro, M. Raponi, D. I. Wilson, and D. Baralle, “BRCA1 exon 11 alternative splicing, multiple functions and the association with cancer,” Biochemical Society Transactions, vol. 40, no. 4, pp. 768–772, 2012. View at Publisher · View at Google Scholar
  33. J. Zhong, R. X. Cao, X. Y. Zu et al., “Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma,” FEBS Journal, vol. 279, no. 2, pp. 316–335, 2012. View at Publisher · View at Google Scholar
  34. H. Albert, S. Santos, E. Battaglia, M. Brito, C. Monteiro, and D. Bagrel, “Differential expression of CDC25 phosphatases splice variants in human breast cancer cells,” Clinical Chemistry and Laboratory Medicine, vol. 49, no. 10, pp. 1707–1714, 2011.
  35. S. Sebban, R. Golan-Gerstl, R. Karni, O. Vaksman, B. Davidson, and R. Reich, “Alternatively spliced lysyl oxidase-like 4 isoforms have a pro-metastatic role in cancer,” Clinical and Experimental Metastasis, vol. 30, no. 1, pp. 103–117, 2013. View at Publisher · View at Google Scholar
  36. Y. Wang, D. W. Chan, V. W. S. Liu, P. M. Chiu, and H. Y. S. Ngan, “Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis,” Clinical Cancer Research, vol. 16, no. 9, pp. 2529–2539, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Haile and M. D. Sadar, “Androgen receptor and its splice variants in prostate cancer,” Cellular and Molecular Life Sciences, vol. 68, no. 24, pp. 3971–3981, 2011. View at Publisher · View at Google Scholar
  38. P. A. Usher, A. M. Sieuwerts, A. Bartels et al., “Identification of alternatively spliced TIMP-1 mRNA in cancer cell lines and colon cancer tissue,” Molecular Oncology, vol. 1, no. 2, pp. 205–215, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. D. C. Gotley, J. Fawcett, M. D. Walsh, J. A. Reeder, D. L. Simmons, and T. M. Antalis, “Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer,” British Journal of Cancer, vol. 74, no. 3, pp. 342–351, 1996. View at Scopus
  40. R. Pio and L. M. Montuenga, “Alternative splicing in lung cancer,” Journal of Thoracic Oncology, vol. 4, no. 6, pp. 674–678, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. D. Moretti, B. Del Bello, E. Cosci, M. Biagioli, C. Miracco, and E. Maellaro, “Novel variants of muscle calpain 3 identified in human melanoma cells: cisplatin-induced changes in vitro and differential expression in melanocytic lesions,” Carcinogenesis, vol. 30, no. 6, pp. 960–967, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. N. Hanoun, C. Bureau, T. Diab et al., “The SV2 variant of KLF6 is down-regulated in hepatocellular carcinoma and displays anti-proliferative and pro-apoptotic functions,” Journal of Hepatology, vol. 53, no. 5, pp. 880–888, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. Q. Yi and L. Tang, “Alternative spliced variants as biomarkers of colorectal cancer,” Current Drug Metabolism, vol. 12, no. 10, pp. 966–974, 2011. View at Publisher · View at Google Scholar
  44. G. S. Omenn, A. K. Yocum, and R. Menon, “Alternative splice variants, a new class of protein cancer biomarker candidates: findings in pancreatic cancer and breast cancer with systems biology implications,” Disease Markers, vol. 28, no. 4, pp. 241–251, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Lee, E. R. Gamazon, E. Rebman et al., “Variants affecting exon skipping contribute to complex traits,” PLOS Genetics, vol. 8, no. 10, Article ID e1002998, 2012.
  46. H. Feng, Z. Qin, and X. Zhang, “Opportunities and methods for studying alternative splicing in cancer with RNA-Seq,” Cancer Letters, 2012. View at Publisher · View at Google Scholar
  47. G. Li, J. H. Bahn, J. H. Lee et al., “Identification of allele-specific alternative mRNA processing via transcriptome sequencing,” Nucleic Acids Research, vol. 40, no. 13, article e104, 2012.
  48. L. Xi, A. Feber, V. Gupta et al., “Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer,” Nucleic Acids Research, vol. 36, no. 20, pp. 6535–6547, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Ben-Dov, B. Hartmann, J. Lundgren, and J. Valcárcel, “Genome-wide analysis of alternative pre-mRNA splicing,” Journal of Biological Chemistry, vol. 283, no. 3, pp. 1229–1233, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. O. Gautschi, D. Ratschiller, M. Gugger, D. C. Betticher, and J. Heighway, “Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation,” Lung Cancer, vol. 55, no. 1, pp. 1–14, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. G. Lamolle, M. Marin, and F. Alvarez-Valin, “Silent mutations in the gene encoding the p53 protein are preferentially located in conserved amino acid positions and splicing enhancers,” Mutation Research, vol. 600, no. 1-2, pp. 102–112, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. D. W. Neklason, C. H. Solomon, A. L. Dalton, S. K. Kuwada, and R. W. Burt, “Intron 4 mutation in APC gene results in splice defect and attenuated FAP phenotype,” Familial Cancer, vol. 3, no. 1, pp. 35–40, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Raponi, J. Kralovicova, E. Copson et al., “Prediction of single-nucleotide substitutions that result in exon skipping: identification of a splicing silencer in BRCA1 exon 6,” Human Mutation, vol. 32, no. 4, pp. 436–444, 2011. View at Publisher · View at Google Scholar · View at Scopus
  54. H. X. Liu, L. Cartegni, M. Q. Zhang, and A. R. Krainer, “A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes,” Nature Genetics, vol. 27, no. 1, pp. 55–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Narla, A. DiFeo, H. L. Reeves et al., “A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk,” Cancer Research, vol. 65, no. 4, pp. 1213–1222, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. G. Narla, A. Difeo, S. Yao et al., “Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread,” Cancer Research, vol. 65, no. 13, pp. 5761–5768, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. A. DiFeo, L. Feld, E. Rodriguez et al., “A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response,” Cancer Research, vol. 68, no. 4, pp. 965–970, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. J. O. Yang, W. Y. Kim, and J. Bhak, “ssSNPTarget: genome-wide splice-site single nucleotide polymorphism database,” Human Mutation, vol. 30, no. 12, pp. E1010–E1020, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. A. G. Douglas and M. J. Wood, “RNA splicing: disease and therapy,” Briefings in Functional Genomics, vol. 10, no. 3, pp. 151–164, 2011. View at Publisher · View at Google Scholar
  60. R. K. Singh and T. A. Cooper, “Pre-mRNA splicing in disease and therapeutics,” Trends in Molecular Medicine, vol. 18, no. 8, pp. 472–482, 2012. View at Publisher · View at Google Scholar
  61. P. Spitali and A. Aartsma-Rus, “Splice modulating therapies for human disease,” Cell, vol. 148, no. 6, pp. 1085–1088, 2012. View at Publisher · View at Google Scholar
  62. K. Miura, W. Fujibuchi, and M. Unno, “Splice isoforms as therapeutic targets for colorectal cancer,” Carcinogenesis, vol. 33, no. 12, pp. 2311–2319, 2012. View at Publisher · View at Google Scholar
  63. J. P. Maciejewski and R. A. Padgett, “Defects in spliceosomal machinery: a new pathway of leukaemogenesis,” British Journal of Haematology, vol. 158, no. 2, pp. 165–173, 2012. View at Publisher · View at Google Scholar
  64. M. Hagiwara, “Alternative splicing: a new drug target of the post-genome era,” Biochimica et Biophysica Acta, vol. 1754, no. 1-2, pp. 324–331, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. C. A. Blair and X. Zi, “Potential molecular targeting of splice variants for cancer treatment,” Indian Journal of Experimental Biology, vol. 49, no. 11, pp. 836–839, 2011.
  66. R. J. Van Alphen, E. A. C. Wiemer, H. Burger, and F. A. L. M. Eskens, “The spliceosome as target for anticancer treatment,” British Journal of Cancer, vol. 100, no. 2, pp. 228–232, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Bonnal, L. Vigevani, and J. Valcarcel, “The spliceosome as a target of novel antitumour drugs,” Nature Reviews Drug Discovery, vol. 11, no. 11, pp. 847–859, 2012. View at Publisher · View at Google Scholar
  68. E. S. Barrie, R. M. Smith, J. C. Sanford, and W. Sadee, “mRNA transcript diversity creates new opportunities for pharmacological intervention,” Molecular Pharmacology, vol. 81, no. 5, pp. 620–630, 2012. View at Publisher · View at Google Scholar
  69. M. L. Zhang, C. L. Lorson, E. J. Androphy, and J. Zhou, “An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA,” Gene Therapy, vol. 8, no. 20, pp. 1532–1538, 2001. View at Publisher · View at Google Scholar · View at Scopus
  70. C. Andreassi, J. Jarecki, J. Zhou et al., “Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients,” Human Molecular Genetics, vol. 10, no. 24, pp. 2841–2849, 2001. View at Scopus
  71. M. R. Lunn, D. E. Root, A. M. Martino et al., “Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism,” Chemistry and Biology, vol. 11, no. 11, pp. 1489–1493, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Xu, X. Chen, S. M. Grzeschik, M. Ganta, and C. H. Wang, “Hydroxyurea enhances SMN2 gene expression through nitric oxide release,” Neurogenetics, vol. 12, no. 1, pp. 19–24, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. C. C. Weihl, A. M. Connolly, and A. Pestronk, “Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy,” Neurology, vol. 67, no. 3, pp. 500–501, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Y. Yuo, H. H. Lin, Y. S. Chang, W. K. Yang, and J. G. Chang, “5-(N-ethyl-N-isopropyl)-amiloride enhances SMN2 exon 7 inclusion and protein expression in spinal muscular atrophy cells,” Annals of Neurology, vol. 63, no. 1, pp. 26–34, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Andreassi, C. Angelozzi, F. D. Tiziano et al., “Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy,” European Journal of Human Genetics, vol. 12, no. 1, pp. 59–65, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. Zhang, O. Kelemen, M. A. Van Santen et al., “Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon 7 into the SMN (survival of motoneuron) pre-mRNA,” Journal of Biological Chemistry, vol. 286, no. 12, pp. 10126–10136, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. I. S. K. Harahap, T. Saito, L. P. San et al., “Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines,” Brain and Development, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. S. Zheng, Y. Chen, C. P. Donahue, M. S. Wolfe, and G. Varani, “Structural Basis for Stabilization of the Tau Pre-mRNA Splicing Regulatory Element by Novantrone (Mitoxantrone),” Chemistry and Biology, vol. 16, no. 5, pp. 557–566, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. J. S. Lewis and V. C. Jordan, “Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance,” Mutation Research, vol. 591, no. 1-2, pp. 247–263, 2005. View at Publisher · View at Google Scholar · View at Scopus
  80. S. L. Lin, L. Y. Yan, X. T. Zhang et al., “ER-α36, a variant of ER-α, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways,” PLoS ONE, vol. 5, no. 2, Article ID e9013, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. E. Zaharieva, J. K. Chipman, and M. Soller, “Alternative splicing interference by xenobiotics,” Toxicology, vol. 296, pp. 1–12, 2012. View at Publisher · View at Google Scholar
  82. D. Kaida, H. Motoyoshi, E. Tashiro et al., “Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA,” Nature Chemical Biology, vol. 3, no. 9, pp. 576–583, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. Y. Kotake, K. Sagane, T. Owa et al., “Splicing factor SF3b as a target of the antitumor natural product pladienolide,” Nature Chemical Biology, vol. 3, no. 9, pp. 570–575, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. L. Fan, C. Lagisetti, C. C. Edwards, T. R. Webb, and P. M. Potter, “Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing,” ACS Chemical Biology, vol. 6, no. 6, pp. 582–589, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Corrionero, B. Miñana, and J. Valcárcel, “Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A,” Genes and Development, vol. 25, no. 5, pp. 445–459, 2011. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Furumai, K. Uchida, Y. Komi et al., “Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF,” Cancer Science, vol. 101, no. 11, pp. 2483–2489, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. H. Nakajima, B. Sato, T. Fujita, S. Takase, H. Terano, and M. Okuhara, “New antitumor substances, FR901463, FR901464 and FR901465: I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities,” Journal of Antibiotics, vol. 49, no. 12, pp. 1196–1203, 1996. View at Scopus
  88. B. J. Albert, P. A. McPherson, K. O'Brien et al., “Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells,” Molecular Cancer Therapeutics, vol. 8, no. 8, pp. 2308–2318, 2009. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Woolard, W. Vousden, S. J. Moss et al., “Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms,” Chemical Science, vol. 2011, no. 2, pp. 273–278, 2011.
  90. U. Shamim, S. Hanif, A. Albanyan et al., “Resveratrol-induced apoptosis is enhanced in low pH environments associated with cancer,” Journal of Cellular Physiology, vol. 227, no. 4, pp. 1493–1500, 2012. View at Publisher · View at Google Scholar
  91. J. Jakubikova, D. Cervi, M. Ooi et al., “Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma,” Haematologica, vol. 96, no. 8, pp. 1170–1179, 2011. View at Publisher · View at Google Scholar
  92. M. A. Markus, F. Z. Marques, and B. J. Morris, “Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs,” PLoS One, vol. 6, no. 12, Article ID e28926, 2011.
  93. K. Miura, W. Fujibuchi, and M. Unno, “Splice variants in apoptotic pathway,” Experimental Oncology, vol. 34, no. 3, pp. 212–217, 2012.
  94. C. Schwerk and K. Schulze-Osthoff, “Regulation of apoptosis by alternative pre-mRNA splicing,” Molecular Cell, vol. 19, no. 1, pp. 1–13, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. L. Shkreta, U. Froehlich, E. R. Paquet, J. Toutant, S. A. Elela, and B. Chabot, “Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes,” Molecular Cancer Therapeutics, vol. 7, no. 6, pp. 1398–1409, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. J. Lee, J. Zhou, X. Zheng et al., “Identification of a novel cis-element that regulates alternative splicing of Bcl-x pre-mRNA,” Biochemical and Biophysical Research Communications, vol. 420, no. 2, pp. 467–472, 2012. View at Publisher · View at Google Scholar
  97. T. Revil, J. Toutant, L. Shkreta, D. Garneau, P. Cloutier, and B. Chabot, “Protein kinase C-dependent control of Bcl-x alternative splicing,” Molecular and Cellular Biology, vol. 27, no. 24, pp. 8431–8441, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. J. C. Shultz, R. W. Goehe, D. S. Wijesinghe et al., “Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a,” Cancer Research, vol. 70, no. 22, pp. 9185–9196, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. C. Puppin, N. Passon, A. Franzoni, D. Russo, and G. Damante, “Histone deacetylase inhibitors control the transcription and alternative splicing of prohibitin in thyroid tumor cells,” Oncology Reports, vol. 25, no. 2, pp. 393–397, 2011. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Wu, C. Li, W. Huang, W. Li, and R. W. Li, “Alternative splicing regulated by butyrate in bovine epithelial cells,” PLoS One, vol. 7, no. 6, Article ID e39182, 2012.
  101. C. Lee and Q. Wang, “Bioinformatics analysis of alternative splicing,” Briefings in Bioinformatics, vol. 6, no. 1, pp. 23–33, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. L. D. Florea, “Bioinformatics of alternative splicing and its regulation,” Briefings in Bioinformatics, vol. 7, no. 1, pp. 55–69, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. N. Kim and C. Lee, “Bioinformatics detection of alternative splicing,” Methods in Molecular Biology, vol. 452, pp. 179–197, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. H. Ji, Q. Zhou, F. Wen, H. Xia, X. Lu, and Y. Li, “AsMamDB: an alternative splice database of mammals,” Nucleic Acids Research, vol. 29, no. 1, pp. 260–263, 2001. View at Scopus
  105. Y. H. Huang, Y. T. Chen, J. J. Lai, S. T. Yang, and U. C. Yang, “PALS db: putative alternative splicing database,” Nucleic Acids Research, vol. 30, no. 1, pp. 186–190, 2002. View at Scopus
  106. C. Lee, L. Atanelov, B. Modrek, and Y. Xing, “ASAP: the alternative splicing annotation project,” Nucleic Acids Research, vol. 31, no. 1, pp. 101–105, 2003. View at Publisher · View at Google Scholar · View at Scopus
  107. H. Pospisil, A. Herrmann, R. H. Bortfeldt, and J. G. Reich, “EASED: Extended Alternatively Spliced EST Database,” Nucleic Acids Research, vol. 32, pp. D70–D74, 2004. View at Scopus
  108. F. R. Hsu, H. Y. Chang, Y. L. Lin et al., “AVATAR: a database for genome-wide alternative splicing event detection using large scale ESTs and mRNAs,” , Bioinformation, vol. 1, no. 1, pp. 16–18, 2005. View at Publisher · View at Google Scholar
  109. C. L. Zheng, Y. S. Kwon, L. I. Hai-Ri et al., “MAASE: an alternative splicing database designed for supporting splicing microarray applications,” RNA, vol. 11, no. 12, pp. 1767–1776, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. H. Zhang, J. Hu, M. Recce, and B. Tian, “PolyA_DB: a database for mammalian mRNA polyadenylation,” Nucleic Acids Research, vol. 33, pp. D116–D120, 2005. View at Publisher · View at Google Scholar · View at Scopus
  111. V. Le Texier, J. J. Riethoven, V. Kumanduri et al., “AltTrans: transcript pattern variants annotated for both alternative splicing and alternative polyadenylation,” BMC Bioinformatics, vol. 7, article 169, 2006. View at Publisher · View at Google Scholar · View at Scopus
  112. R. Kostadinov, N. Malhotra, M. Viotti, R. Shine, L. D'Antonio, and P. Bagga, “GRSDB: a database of quadruplex forming G-rich sequences in alternatively processed mammalian pre-mRNA sequences,” Nucleic Acids Research, vol. 34, pp. D119–124, 2006. View at Scopus
  113. D. Holste, G. Huo, V. Tung, and C. B. Burge, “HOLLYWOOD: a comparative relational database of alternative splicing,” Nucleic Acids Research, vol. 34, pp. D56–62, 2006. View at Scopus
  114. S. Stamm, J. J. Riethoven, V. Le Texier et al., “ASD: a bioinformatics resource on alternative splicing,” Nucleic Acids Research, vol. 34, pp. D46–55, 2006. View at Scopus
  115. D. Rambaldi, B. Felice, V. Praz, P. Bucher, D. Cittaro, and A. Guffanti, “Splicy: a web-based tool for the prediction of possible alternative splicing events from Affymetrix probeset data,” BMC Bioinformatics, vol. 8, no. 1, article no. S17, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. S. Foissac and M. Sammeth, “ASTALAVISTA: dynamic and flexible analysis of alternative splicing events in custom gene datasets,” Nucleic Acids Research, vol. 35, pp. W297–299, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. Z. Lacroix, C. Legendre, L. Raschid, and B. Snyder, “BIPASS: BioInformatics Pipeline Alternative Splicing Services,” Nucleic Acids Research, vol. 35, pp. W292–296, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. Y. Lee, Y. Lee, B. Kim et al., “ECgene: an alternative splicing database update,” Nucleic Acids Research, vol. 35, no. 1, pp. D99–D103, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. A. Bhasi, R. V. Pandey, S. P. Utharasamy, and P. Senapathy, “EuSplice: a unified resource for the analysis of splice signals and alternative splicing in eukaryotic genes,” Bioinformatics, vol. 23, no. 14, pp. 1815–1823, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. M. C. Ryan, B. R. Zeeberg, N. J. Caplen et al., “SpliceCenter: a suite of web-based bioinformatic applications for evaluating the impact of alternative splicing on RT-PCR, RNAi, microarray, and peptide-based studies,” BMC Bioinformatics, vol. 9, article 313, 2008. View at Publisher · View at Google Scholar · View at Scopus
  121. T. Castrignanò, M. D'Antonio, A. Anselmo et al., “ASPicDB: a database resource for alternative splicing analysis,” Bioinformatics, vol. 24, no. 10, pp. 1300–1304, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. J. M. Bechtel, P. Rajesh, I. Ilikchyan et al., “The Alternative Splicing Mutation Database: a hub for investigations of alternative splicing using mutational evidence,” BMC Research Notes, vol. 1, article 3, 2008. View at Publisher · View at Google Scholar · View at Scopus
  123. F. Birzele, R. Küffner, F. Meier, F. Oefinger, C. Potthast, and R. Zimmer, “ProSAS: a database for analyzing alternative splicing in the context of protein structures,” Nucleic Acids Research, vol. 36, no. 1, pp. D63–D68, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Floris, M. Orsini, and T. A. Thanaraj, “Splice-mediated variants of proteins (SpliVaP)—data and characterization of changes in signatures among protein isoforms due to alternative splicing,” BMC Genomics, vol. 9, article 453, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. A. Bhasi, P. Philip, V. T. Sreedharan, and P. Senapathy, “AspAlt: a tool for inter-database, inter-genomic and user-specific comparative analysis of alternative transcription and alternative splicing in 46 eukaryotes,” Genomics, vol. 94, no. 1, pp. 48–54, 2009. View at Publisher · View at Google Scholar · View at Scopus
  126. G. Koscielny, V. L. Texier, C. Gopalakrishnan et al., “ASTD: the Alternative Splicing and Transcript Diversity database,” Genomics, vol. 93, no. 3, pp. 213–220, 2009. View at Publisher · View at Google Scholar · View at Scopus
  127. R. Sinha, T. Lenser, N. Jahn et al., “TassDB2: a comprehensive database of subtle alternative splicing events,” BMC Bioinformatics, vol. 11, article 216, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. J. I. Takeda, Y. Suzuki, R. Sakate et al., “H-DBAS: Human-transcriptome database for alternative splicing: update 2010,” Nucleic Acids Research, vol. 38, no. 1, Article ID gkp984, pp. D86–D90, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. J. E. Kroll, P. A. Galante, D. T. Ohara, F. C. Navarro, L. Ohno-Machado, and S. J. de Souza, “SPLOOCE: a new portal for the analysis of human splicing variants,” RNA Biology, vol. 9, no. 11, pp. 1339–1343, 2012.
  130. J. M. Rodriguez, P. Maietta, I. Ezkurdia et al., “APPRIS: annotation of principal and alternative splice isoforms,” Nucleic Acids Research, vol. 41, pp. 110–117, 2013. View at Publisher · View at Google Scholar
  131. F. Piva, M. Giulietti, A. B. Burini, and G. Principato, “SpliceAid 2: a database of human splicing factors expression data and RNA target motifs,” Human Mutation, vol. 33, no. 1, pp. 81–85, 2012. View at Publisher · View at Google Scholar
  132. E. Wingender, T. Schoeps, and J. Donitz, “TFClass: an expandable hierarchical classification of human transcription factors,” Nucleic Acids Research, vol. 41, pp. 165–170, 2013. View at Publisher · View at Google Scholar