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Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige

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Abstract

Maintenance of oxygen homeostasis is an indispensable criterion for the existence of multicellular life-forms. Disruption of this homeostasis due to inadequate oxygenation of the respiring tissues leads to pathological hypoxia, which acts as a significant stressor in several pathophysiological conditions including cancer, cardiovascular defects, bacterial infections, and neurological disorders. Consequently, the hypoxic tissues develop necessary adaptations both at the tissue and cellular level. The cellular adaptations involve a dramatic alteration in gene expression, post-transcriptional and post-translational modification of gene products, bioenergetics, and metabolism. Among the key responses to oxygen-deprivation is the skewing of cellular alternative splicing program. Herein, we discuss the current concepts of oxygen tension-dependent alternative splicing relevant to various pathophysiological conditions. Following a brief description of cellular response to hypoxia and the pre-mRNA splicing mechanism, we outline the impressive number of hypoxia-elicited alternative splicing events associated with maladies like cancer, cardiovascular diseases, and neurological disorders. Furthermore, we discuss how manipulation of hypoxia-induced alternative splicing may pose promising strategies for novel translational diagnosis and therapeutic interventions.

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References

  1. David CJ, Manley JL (2010) Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 24(21):2343–2364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dales J-P, Beaufils N, Silvy M, Picard C, Pauly V, Pradel V, Formisano-Tréziny C, Bonnier P, Giusiano S, Charpin C (2010) Hypoxia inducible factor 1α gene (HIF-1α) splice variants: potential prognostic biomarkers in breast cancer. BMC Med 8(1):44

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fandrey J (1995) Hypoxia-inducible gene expression. Respir Physiol 101(1):1–10

    Article  CAS  PubMed  Google Scholar 

  4. Goldberg MA, Dunning SP, Bunn HF (1988) Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 242(4884):1412–1415

    Article  CAS  PubMed  Google Scholar 

  5. Semenza G, Roth P, Fang H, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Semenza GL (1996) Transcriptional regulation by hypoxia-inducible factor 1 molecular mechanisms of oxygen homeostasis. Trends Cardiovasc Med 6(5):151–157

    Article  CAS  PubMed  Google Scholar 

  7. Jiang B-H, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol-Cell Physiol 271(4):C1172–C1180

    Article  CAS  Google Scholar 

  8. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414(6863):550–554

    Article  CAS  PubMed  Google Scholar 

  9. Kaelin W Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402

    Article  CAS  PubMed  Google Scholar 

  10. Kaelin WG Jr (2005) Proline hydroxylation and gene expression. Annu Rev Biochem 74:115–128

    Article  CAS  PubMed  Google Scholar 

  11. Wang GL, Jiang B-H, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Nat Acad Sci 92(12):5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tian H (1998) Hammer RE, Matsumoto AM, Russell DW, and McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12:3320–3324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F (2002) Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8(7):702–710

    Article  CAS  PubMed  Google Scholar 

  14. Peng J, Zhang L, Drysdale L, Fong G-H (2000) The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc Natl Acad Sci 97(15):8386–8391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA (2003) The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice. Blood 102(5):1634–1640

    Article  CAS  PubMed  Google Scholar 

  16. Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg Å, Gradin K (2006) Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 10(5):413–423

    Article  CAS  PubMed  Google Scholar 

  17. Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K, Whitelaw ML, Peet DJ (2006) Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J Biol Chem 281(32):22575–22585

    Article  CAS  PubMed  Google Scholar 

  18. Liu F, Huang X, Luo Z, He J, Haider F, Song C, Peng L, Chen T, Wu B (2019) Hypoxia-activated PI3K/Akt inhibits oxidative stress via the regulation of reactive oxygen species in human dental pulp cells. Oxid Med Cell Longev 2019:1

    Google Scholar 

  19. Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J, Michiels C (2000) ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett 468(1):53–58

    Article  CAS  PubMed  Google Scholar 

  20. Mingyuan X, Qianqian P, Shengquan X, Chenyi Y, Rui L, Yichen S, Jinghong X (2018) Hypoxia-inducible factor-1α activates transforming growth factor-β1/Smad signaling and increases collagen deposition in dermal fibroblasts. Oncotarget 9(3):3188

    Article  PubMed  Google Scholar 

  21. Xu W, Zhou W, Cheng M, Wang J, Liu Z, He S, Luo X, Huang W, Chen T, Yan W (2017) Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. Sci Rep 7(1):1–13

    Google Scholar 

  22. D’Ignazio L, Bandarra D, Rocha S (2016) NF-κB and HIF crosstalk in immune responses. FEBS J 283(3):413–424

    Article  CAS  PubMed  Google Scholar 

  23. Koong AC, Chen EY, Giaccia AJ (1994) Hypoxia causes the activation of nuclear factor κB through the phosphorylation of IκBα on tyrosine residues. Can Res 54(6):1425–1430

    CAS  Google Scholar 

  24. Agani F, Jiang B-H (2013) Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets 13(3):245–251

    Article  CAS  PubMed  Google Scholar 

  25. Du J, Xu R, Hu Z, Tian Y, Zhu Y, Gu L, Zhou L (2011) PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1α expression in MCF-7 breast cancer cells. PLoS ONE 6(9):e25213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Patel AA, Steitz JA (2003) Splicing double: insights from the second spliceosome. Nat Rev Mol Cell Biol 4(12):960–970

    Article  CAS  PubMed  Google Scholar 

  27. Hall SL, Padgett RA (1994) Conserved sequences in a class of rare eukaryotic nuclear introns with non-consensus splice sites. Elsevier, Amsterdam

    Book  Google Scholar 

  28. Burge CB, Padgett RA, Sharp PA (1998) Evolutionary fates and origins of U12-type introns. Mol Cell 2(6):773–785

    Article  CAS  PubMed  Google Scholar 

  29. Dvinge H, Kim E, Abdel-Wahab O, Bradley RK (2016) RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 16(7):413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Scotti MM, Swanson MS (2016) RNA mis-splicing in disease. Nat Rev Genet 17(1):19

    Article  CAS  PubMed  Google Scholar 

  31. Krecic AM, Swanson MS (1999) hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol 3(11):363–371

    Article  Google Scholar 

  32. Long JC, Caceres JF (2009) The SR protein family of splicing factors: master regulators of gene expression. Biochem J 417(1):15–27

    Article  CAS  PubMed  Google Scholar 

  33. Dasgupta T, Ladd AN (2012) The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. Wiley Interdisciplin Rev RNA 3(1):104–121

    Article  CAS  Google Scholar 

  34. Konieczny P, Stepniak-Konieczna E, Sobczak K (2014) MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res 42(17):10873–10887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sutherland LC, Rintala-Maki ND, White RD, Morin CD (2005) RNA binding motif (RBM) proteins: a novel family of apoptosis modulators? J Cell Biochem 94(1):5–24

    Article  CAS  PubMed  Google Scholar 

  36. Ule J, Stefani G, Mele A, Ruggiu M, Wang X, Taneri B, Gaasterland T, Blencowe BJ, Darnell RB (2006) An RNA map predicting Nova-dependent splicing regulation. Nature 444(7119):580–586

    Article  CAS  PubMed  Google Scholar 

  37. Fu X-D, Ares M Jr (2014) Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet 15(10):689–701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pan Q (2008) Shai, o., lee, lJ, Frey, bJ & blencowe, bJ (2008). Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40:1413–1415

    Article  CAS  PubMed  Google Scholar 

  39. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456(7221):470–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Biamonti G, Bonomi S, Gallo S, Ghigna C (2012) Making alternative splicing decisions during epithelial-to-mesenchymal transition (EMT). Cell Mol Life Sci 69(15):2515–2526

    Article  CAS  PubMed  Google Scholar 

  41. Sveen A, Kilpinen S, Ruusulehto A, Lothe R, Skotheim RI (2016) Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35(19):2413–2427

    Article  CAS  PubMed  Google Scholar 

  42. Venables JP, Klinck R, Koh C, Gervais-Bird J, Bramard A, Inkel L, Durand M, Couture S, Froehlich U, Lapointe E (2009) Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 16(6):670

    Article  CAS  PubMed  Google Scholar 

  43. Kanopka A (2017) Cell survival: Interplay between hypoxia and pre-mRNA splicing. Exp Cell Res 356(2):187–191

    Article  CAS  PubMed  Google Scholar 

  44. Nakayama K, Kataoka N (2019) Regulation of gene expression under hypoxic conditions. Int J Mol Sci 20(13):3278

    Article  CAS  PubMed Central  Google Scholar 

  45. Farina AR, Cappabianca L, Sebastiano M, Zelli V, Guadagni S, Mackay AR (2020) Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer. J Exp Clin Cancer Res 39(1):1–30

    Article  Google Scholar 

  46. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Meta Rev 26(2):225–239

    Article  CAS  Google Scholar 

  47. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  48. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  49. Ghigna C, Valacca C, Biamonti G (2008) Alternative splicing and tumor progression. Curr Genomics 9(8):556–570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu Z, Han L, Dong Y, Tan Y, Li Y, Zhao M, Xie H, Ju H, Wang H, Zhao Y (2016) EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis. Oncotarget 7(4):4680

    Article  PubMed  Google Scholar 

  51. Mardy S, Miura Y, Endo F, Matsuda I, Sztriha L, Frossard P, Moosa A, Ismail EA, Macaya A, Andria G (1999) Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. AM J Hum Genet 64(6):1570–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Riffo-Campos ÁL, Gimeno-Valiente F, Rodríguez FM, Cervantes A, López-Rodas G, Franco L, Castillo J (2018) Role of epigenetic factors in the selection of the alternative splicing isoforms of human KRAS in colorectal cancer cell lines. Oncotarget 9(29):20578

    Article  PubMed  PubMed Central  Google Scholar 

  53. Voice JK, Klemke RL, Le A, Jackson JH (1999) Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274(24):17164–17170

    Article  CAS  PubMed  Google Scholar 

  54. Plowman SJ, Arends MJ, Brownstein DG, Luo F, Devenney PS, Rose L, Ritchie A-M, Berry RL, Harrison DJ, Hooper ML (2006) The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice. Exp Cell Res 312(1):16–26

    Article  CAS  PubMed  Google Scholar 

  55. Luo F, Ye H, Hamoudi R, Dong G, Zhang W, Patek CE, Poulogiannis G, Arends MJ (2010) K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation. J Pathol J Pathol Soc GB Irel 220(5):542–550

    CAS  Google Scholar 

  56. Sena JA, Wang L, Heasley LE, Hu C-J (2014) Hypoxia regulates alternative splicing of HIF and non-HIF target genes. Mol Cancer Res 12(9):1233–1243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Plowman S, Berry R, Bader S, Luo F, Arends M, Harrison D, Hooper M, Patek C (2006) K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. J Exp Clin Cancer Res 25(2):259–267

    CAS  PubMed  Google Scholar 

  58. Chen W-C, To MD, Westcott PM, Delrosario R, Kim I-J, Philips M, Tran Q, Bayani N, Balmain A (2019) Regulation of KRAS4A/B splicing in cancer stem cells by the RBM39 splicing complex. Preprint at bioRxiv. https://doi.org/10.1101/646125

  59. Bowler E, Porazinski S, Uzor S, Thibault P, Durand M, Lapointe E, Rouschop KM, Hancock J, Wilson I, Ladomery M (2018) Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells. BMC cancer 18(1):355

    Article  PubMed  PubMed Central  Google Scholar 

  60. Huan L, Guo T, Wu Y, Xu L, Huang S, Xu Y, Liang L, He X (2020) Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response. Mol Cancer 19(1):1–17

    Article  Google Scholar 

  61. Ramchandani D, Unruh D, Lewis CS, Bogdanov VY, Weber GF (2016) Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions. Lab Invest 96(12):1234–1245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gupta GP, Massagué J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695

    Article  CAS  PubMed  Google Scholar 

  63. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12(8):895–904

    Article  CAS  PubMed  Google Scholar 

  64. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Investig 119(6):1438–1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110

    Article  PubMed  Google Scholar 

  66. Ahuja N, Ashok C, Natua S, Pant D, Cherian A, Pandkar MR, Yadav P, Narayanan SSV, Mishra J, Samaiya A, Shukla S (2020) Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer. NAR Cancer 2(3):1–17

    Article  Google Scholar 

  67. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4(1):33–45

    Article  CAS  PubMed  Google Scholar 

  68. Auvinen P, Tammi R, Tammi M, Johansson R, Kosma VM (2005) Expression of CD44s, CD44v3 and CD44v6 in benign and malignant breast lesions: correlation and colocalization with hyaluronan. Histopathology 47(4):420–428

    Article  CAS  PubMed  Google Scholar 

  69. Saito S, Okabe H, Watanabe M, Ishimoto T, Iwatsuki M, Baba Y, Tanaka Y, Kurashige J, Miyamoto Y, Baba H (2013) CD44v6 expression is related to mesenchymal phenotype and poor prognosis in patients with colorectal cancer. Oncol Rep 29(4):1570–1578

    Article  CAS  PubMed  Google Scholar 

  70. Krishnamachary B, Penet M-F, Nimmagadda S, Mironchik Y, Raman V, Solaiyappan M, Semenza GL, Pomper MG, Bhujwalla ZM (2012) Hypoxia regulates CD44 and its variant isoforms through HIF-1α in triple negative breast cancer. PLoS ONE 7(8):e44078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Babic A (1998) Kiree a ML, Kolesniko a TV and Lau LF: CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 95:6355–6360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Huang Y-T, Lan Q, Lorusso G, Duffey N, Rüegg C (2017) The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget 8(6):9200

    Article  PubMed  Google Scholar 

  73. Hirschfeld M, zur Hausen A, Bettendorf H, Jäger M, Stickeler E, (2009) Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Can Res 69(5):2082–2090

    Article  CAS  Google Scholar 

  74. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–30

    Article  CAS  PubMed  Google Scholar 

  75. McCarthy N (2008) ALK takes the rap. Nat Rev Cancer 8(11):833–833

    Article  CAS  Google Scholar 

  76. Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1α versus HIF-2α in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Can Res 66(12):6264–6270

    Article  CAS  Google Scholar 

  77. Nowak D, Amin E, Rennel E, Hoareau-Aveilla C (2010) Gam¬ mons M, Damodoran G, Hagiwara M. Harper SJ, Woolard J, Ladomery MR, Bates DO Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angio genesis. J Biol Chem 285:5532–5540

    Article  CAS  PubMed  Google Scholar 

  78. Houck KA, Leung D, Rowland A, Winer J, Ferrara N (1992) Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267(36):26031–26037

    Article  CAS  PubMed  Google Scholar 

  79. Pritchard-Jones R, Dunn D, Qiu Y, Varey A, Orlando A, Rigby H, Harper S, Bates D (2007) Expression of VEGF xxx b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97(2):223–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Barratt SL, Blythe T, Ourradi K, Jarrett C, Welsh GI, Bates DO, Millar AB (2018) Effects of hypoxia and hyperoxia on the differential expression of VEGF-A isoforms and receptors in Idiopathic Pulmonary Fibrosis (IPF). Respir Res 19(1):1–5

    Article  Google Scholar 

  81. Qiu Y, Hoareau-Aveilla C, Oltean S, Harper SJ, Bates DO (2009) The anti-angiogenic isoforms of VEGF in health and disease. Portland Press Ltd.,

  82. Nowak D, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO (2008) Expression of proand anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 121:3487–4349

    Article  CAS  PubMed  Google Scholar 

  83. Jakubauskiene E, Vilys L, Makino Y, Poellinger L, Kanopka A (2015) Increased serine-arginine (SR) protein phosphorylation changes pre-mRNA splicing in hypoxia. J Biol Chem 290(29):18079–18089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hayes GM, Carrigan PE, Miller LJ (2007) Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas. Can Res 67(5):2072–2080

    Article  CAS  Google Scholar 

  85. Semenza GL, Jiang B-H, Leung SW, Passantino R, Concordet J-P, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271(51):32529–32537

    Article  CAS  PubMed  Google Scholar 

  86. Han J, Li J, Ho JC, Chia GS, Kato H, Jha S, Yang H, Poellinger L, Lee KL (2017) Hypoxia is a key driver of alternative splicing in human breast cancer cells. Sci Rep 7(1):1–17

    Google Scholar 

  87. Mazurek S, Boschek CB, Hugo F, Eigenbrodt E (2005) Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin cancer biol 4:300–308

    Article  Google Scholar 

  88. Li Z, Yang P (1846) Li Z (2014) The multifaceted regulation and functions of PKM2 in tumor progression. Biochimica et Biophysica Acta (BBA) Rev Cancer 2:285–296

    Google Scholar 

  89. Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blümlein K, Wanker EE, Ralser M, Cramer T, Adjaye J (2014) HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1–3 and PKM2. Stem Cells 32:364–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Minchenko O, Opentanova I, Caro J (2003) Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase gene family (PFKFB-1–4) expression in vivo. FEBS Lett 554(3):264–270

    Article  CAS  PubMed  Google Scholar 

  92. Minchenko OH, Ogura T, Opentanova IL, Minchenko DO, Esumi H (2005) Splice isoform of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-4: expression and hypoxic regulation. Mol Cell Biochem 280(1–2):227–234

    Article  CAS  PubMed  Google Scholar 

  93. Mykhalchenko V, Minchenko D, Tsuchihara K, Moenner M, Komisarenko S, Bikfalvi A, Esumi H, Minchenko O (2008) Expression of mouse 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 mRNA alternative splice variants in hypoxia. Ukr Biokhim Zh 80(1):19

    CAS  Google Scholar 

  94. Barsoum IB, Koti M, Siemens DR, Graham CH (2014) Mechanisms of hypoxia-mediated immune escape in cancer. Can Res 74(24):7185–7190

    Article  CAS  Google Scholar 

  95. Li Y, Patel SP, Roszik J, Qin Y (2018) Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational immunotherapy. Front immunol 9:1591

    Article  PubMed  PubMed Central  Google Scholar 

  96. Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, Chouaib S (2015) Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am J Physiol-Cell Physiol 309(9):C569–C579

    Article  PubMed  PubMed Central  Google Scholar 

  97. O’Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang J-G, Belz GT (2009) Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461(7264):659–663

    Article  Google Scholar 

  98. Cheng J, Zhou T, Liu C, Shapiro JP, Brauer MJ, Kiefer MC, Barr PJ, Mountz JD (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263(5154):1759–1762

    Article  CAS  PubMed  Google Scholar 

  99. Zheng Z (1994) A complete checklist of species and subspecies of the Chinese birds. Science Press, China

    Google Scholar 

  100. Hohlbaum AM, Moe S, Marshak-Rothstein A (2000) Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J Exp Med 191(7):1209–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Peciuliene I, Vilys L, Jakubauskiene E, Zaliauskiene L, Kanopka A (2019) Hypoxia alters splicing of the cancer associated Fas gene. Exp Cell Res 380(1):29–35

    Article  CAS  PubMed  Google Scholar 

  102. Labiano S, Palazón A, Bolanos E, Azpilikueta A, Sánchez-Paulete AR, Morales-Kastresana A, Quetglas JI, Perez-Gracia JL, Gúrpide A, Rodriguez-Ruiz M (2016) Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism. Oncoimmunology 5(1):e1062967

    Article  PubMed  Google Scholar 

  103. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37(3):299–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nuñez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74(4):597–608

    Article  CAS  PubMed  Google Scholar 

  105. Xerri L, Parc P, Brousset P, Schlaifer D, Hassoun J, Reed JC, Krajewski S, Birnbaum D (1996) Predominant expression of the long isoform of Bcl-x (Bcl-xL) in human lymphomas. Br J Haematol 92(4):900–906

    Article  CAS  PubMed  Google Scholar 

  106. Olopade OI, Adeyanju MO, Safa AR, Hagos F, Mick R, Thompson CB, Recant WM (1997) Overexpression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 3(4):230–237

    CAS  PubMed  Google Scholar 

  107. Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H (2001) Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology 34(1):55–61

    Article  CAS  PubMed  Google Scholar 

  108. Chen N, Chen X, Huang R, Zeng H, Gong J, Meng W, Lu Y, Zhao F, Wang L, Zhou Q (2009) BCL-xL is a target gene regulated by hypoxia-inducible factor-1α. J Biol Chem 284(15):10004–10012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sasabe E, Tatemoto Y, Li D, Yamamoto T, Osaki T (2005) Mechanism of HIF-1α-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells. Cancer Sci 96(7):394–402

    Article  CAS  PubMed  Google Scholar 

  110. Sermeus A, Genin M, Maincent A, Fransolet M, Notte A, Leclere L, Riquier H, Arnould T, Michiels C (2012) Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types. PLoS ONE 7(11):e47519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Xiao Q, Ford AL, Xu J, Yan P, Lee K-Y, Gonzales E, West T, Holtzman DM, Lee J-M (2012) Bcl-x pre-mRNA splicing regulates brain injury after neonatal hypoxia-ischemia. J Neurosci 32(39):13587–13596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stevens M, Oltean S (2019) Modulation of the apoptosis gene Bcl-x function through alternative splicing. Front Genet 10(804):1–9

    Google Scholar 

  113. Bielli P, Bordi M, Biasio VD, Sette C (2014) Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5′ splice site selection. Nucleic Acids Res 42(19):12070–12081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gang H, Hai Y, Dhingra R, Gordon JW, Yurkova N, Aviv Y, Li H, Aguilar F, Marshall A, Leygue E (2011) A novel hypoxia-inducible spliced variant of mitochondrial death gene Bnip3 promotes survival of ventricular myocytes. Circ Res 108(9):1084–1092

    Article  CAS  PubMed  Google Scholar 

  115. Lin J-C, Tsao M-F, Lin Y-J (2016) Differential impacts of alternative splicing networks on apoptosis. Int J Mol Sci 17(12):2097

    Article  PubMed Central  Google Scholar 

  116. Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6(8):611–622

    Article  CAS  PubMed  Google Scholar 

  117. Wright WE, Shay JW (2000) Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 6(8):849–851

    Article  CAS  PubMed  Google Scholar 

  118. Wu K-J, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R (1999) Direct activation of TERT transcription by c-MYC. Nat Genet 21(2):220–224

    Article  CAS  PubMed  Google Scholar 

  119. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR (2001) Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int J Cancer 91(5):644–649

    Article  CAS  PubMed  Google Scholar 

  120. Listerman I, Sun J, Gazzaniga FS, Lukas JL, Blackburn EH (2013) The major reverse transcriptase–incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Can Res 73(9):2817–2828

    Article  CAS  Google Scholar 

  121. Anderson C, Hoare S, Ashcroft M, Bilsland A, Keith W (2006) Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms. Oncogene 25(1):61–69

    Article  CAS  PubMed  Google Scholar 

  122. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1):155–165

    Article  CAS  PubMed  Google Scholar 

  123. Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG (2015) SMN2 splice modulators enhance U1–pre-mRNA association and rescue SMA mice. Nat Chem Biol 11(7):511

    Article  CAS  PubMed  Google Scholar 

  124. Naryshkin NA, Weetall M, Dakka A, Narasimhan J, Zhao X, Feng Z, Ling KK, Karp GM, Qi H, Woll MG (2014) SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345(6197):688–693

    Article  CAS  PubMed  Google Scholar 

  125. Wang J, Schultz PG, Johnson KA (2018) Mechanistic studies of a small-molecule modulator of SMN2 splicing. Proc Natl Acad Sci 115(20):E4604–E4612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bebee TW, Dominguez CE, Samadzadeh-Tarighat S, Akehurst KL, Chandler DS (2012) Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model. Hum Mol Genet 21(19):4301–4313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Manabe T, Katayama T, Sato N, Gomi F, Hitomi J, Yanagita T, Kudo T, Honda A, Mori Y, Matsuzaki S (2003) Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer’s disease. Cell Death Differ 10(6):698–708

    Article  CAS  PubMed  Google Scholar 

  128. Münch C, Bg Z, Leven A, Stamm S, Einkörn H, Schwalenstöcker B, Ludolph AC, Riepe MW, Meyer T (2003) Differential regulation of 5′ splice variants of the glutamate transporter EAAT2 in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid. J Neurosci Res 71(6):819–825

    Article  PubMed  Google Scholar 

  129. Cimarosti H, Jones NM, O’Shea RD, Pow DV, Salbego C, Beart PM (2005) Hypoxic preconditioning in neonatal rat brain involves regulation of excitatory amino acid transporter 2 and estrogen receptor alpha. Neurosci Lett 385(1):52–57

    Article  CAS  PubMed  Google Scholar 

  130. Pow DV, Naidoo T, Lingwood BE, Healy GN, Williams SM, Sullivan RK, O’Driscoll S, Colditz PB (2004) Loss of glial glutamate transporters and induction of neuronal expression of GLT-1B in the hypoxic neonatal pig brain. Dev Brain Res 153(1):1–11

    Article  CAS  Google Scholar 

  131. Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler R, Rothstein J, Traystman RJ (1997) Hypoxia—ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann Neurol Off J Am Neurol Assoc Child Neurol Soc 42(3):335–348

    CAS  Google Scholar 

  132. Xue L-L, Wang F, Xiong L-L, Du R-L, Zhou H-L, Zou Y, Wu M-X, Yang M-A, Dai J, He M-X (2020) A single-nucleotide polymorphism induced alternative splicing in Tacr3 involves in hypoxic-ischemic brain damage. Brain Res Bull 154:106–115

    Article  CAS  PubMed  Google Scholar 

  133. Shimokawa H, Yasuda S (2008) Myocardial ischemia: current concepts and future perspectives. J Cardiol 52(2):67–78

    Article  PubMed  Google Scholar 

  134. Williams AL, Khadka V, Tang M, Avelar A, Schunke KJ, Menor M, Shohet RV (2018) Genomic and “Polyomic” Studies of Cardiovascular and Inflammatory Diseases: HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction. Physiol Genomics 50(7):479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mirtschink P, Krishnan J, Grimm F, Sarre A, Hörl M, Kayikci M, Fankhauser N, Christinat Y, Cortijo C, Feehan O (2015) HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522(7557):444–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Choi Y-J, Kim I, Lee JE, Park J-W (2019) PIN1 transcript variant 2 acts as a long non-coding RNA that controls the HIF-1-driven hypoxic response. Sci Rep 9(1):1–9

    Google Scholar 

  137. Jeong W, Rapisarda A, Park SR, Kinders RJ, Chen A, Melillo G, Turkbey B, Steinberg SM, Choyke P, Doroshow JH (2014) Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors. Cancer Chemother Pharmacol 73(2):343–348

    Article  CAS  PubMed  Google Scholar 

  138. Coltella N, Valsecchi R, Ponente M, Ponzoni M, Bernardi R (2015) Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia. Clin Cancer Res 21(16):3685–3694

    Article  CAS  PubMed  Google Scholar 

  139. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Can Res 64(4):1475–1482

    Article  CAS  Google Scholar 

  140. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Can Res 65(19):9047–9055

    Article  CAS  Google Scholar 

  141. Pang Y, Yang C, Schovanek J, Wang H, Bullova P, Caisova V, Gupta G, Wolf KI, Semenza GL, Zhuang Z (2017) Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway. Oncotarget 8(14):22313

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, Popp FC, Dahlke MH, Piso P, Schlitt HJ, Geissler EK (2007) Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1α autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 13(21):6459–6468

    Article  CAS  PubMed  Google Scholar 

  143. Bohonowych JE, Peng S, Gopal U, Hance MW, Wing SB, Argraves KM, Lundgren K, Isaacs JS (2011) Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation. BMC Cancer 11(1):520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Staab A, Loeffler J, Said HM, Diehlmann D, Katzer A, Beyer M, Fleischer M, Schwab F, Baier K, Einsele H (2007) Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells. BMC Cancer 7(1):1–7

    Article  Google Scholar 

  145. Minegishi H, Fukashiro S, Ban HS, Nakamura H (2013) Discovery of indenopyrazoles as a new class of hypoxia inducible factor (HIF)-1 inhibitors. ACS Med Chem Lett 4(2):297–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lee K, Kang JE, Park S-K, Jin Y, Chung K-S, Kim H-M, Lee K, Kang MR, Lee MK, Song KB (2010) LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line. Biochem Pharmacol 80(7):982–989

    Article  CAS  PubMed  Google Scholar 

  147. Carvalho T, Martins S, Rino J, Marinho S, Carmo-Fonseca M (2017) Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay. J Cell Sci 130(9):1519–1531

    CAS  PubMed  Google Scholar 

  148. Sidarovich A, Will CL, Anokhina MM, Ceballos J, Sievers S, Agafonov DE, Samatov T, Bao P, Kastner B, Urlaub H (2017) Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation. Elife 6:e23533

    Article  PubMed  PubMed Central  Google Scholar 

  149. O’Brien K, Matlin AJ, Lowell AM, Moore MJ (2008) The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing. J Biol Chem 283(48):33147–33154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pawellek A, McElroy S, Samatov T, Mitchell L, Woodland A, Ryder U, Gray D, Lührmann R, Lamond AI (2014) Identification of small molecule inhibitors of pre-mRNA splicing. J Biol Chem 289(50):34683–34698

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bashaw ED, Huang S-M, Coté TR, Pariser AR, Garnett CE, Burckart G, Zhang L, Men AY, Le CD, Charlab R (2011) Clinical pharmacology as a cornerstone of orphan drug development. Nat Rev Drug Discov 10(11):795–796

    Article  CAS  PubMed  Google Scholar 

  152. Zhou HM, Slominski RM, Seymour LJ, Bell MC, Dave P, Atumonye J, Wright W III, Dawes A, Griesenauer B, Paczesny S (2020) Ex vivo culture of mouse skin activates an interleukin 1 alpha-dependent inflammatory response. Exp Dermatol 29(1):102–106

    Article  CAS  PubMed  Google Scholar 

  153. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR (2007) Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 5(4):e73

    Article  PubMed  PubMed Central  Google Scholar 

  154. Matsuo M, Masumura T, Nishio H, Nakajima T, Kitoh Y, Takumi T, Koga J, Nakamura H (1991) Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe. J Clin Investig 87(6):2127–2131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, Van Deutekom J, van Ommen GJ, Den Dunnen JT (2009) Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30(3):293–299

    Article  PubMed  Google Scholar 

  156. Dewaele M, Tabaglio T, Willekens K, Bezzi M, Teo SX, Low DH, Koh CM, Rambow F, Fiers M, Rogiers A (2016) Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth. J Clin Investig 126(1):68–84

    Article  PubMed  Google Scholar 

  157. Rinaldi C, Wood MJ (2018) Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol 14(1):9

    Article  CAS  PubMed  Google Scholar 

  158. Cloe A, Chen L, Li Y, Liu H, Cheng JX (2016) Identification of Specific Hnrnps As Novel Therapeutic Targets and Responsive Indicators of KPT330 (selinexor) in Leukemia. American Society of Hematology, Washington, DC

    Book  Google Scholar 

  159. Deng J, Chen S, Wang F, Zhao H, Xie Z, Xu Z, Zhang Q, Liang P, Zhai X, Cheng Y (2016) Effects of hnRNP A2/B1 knockdown on inhibition of glioblastoma cell invasion, growth and survival. Mol Neurobiol 53(2):1132–1144

    Article  CAS  PubMed  Google Scholar 

  160. Suk F-M, Lin S-Y, Lin R-J, Hsine Y-H, Liao Y-J, Fang S-U, Liang Y-C (2015) Bortezomib inhibits Burkitt’s lymphoma cell proliferation by downregulating sumoylated hnRNP K and c-Myc expression. Oncotarget 6(28):25988

    Article  PubMed  PubMed Central  Google Scholar 

  161. Muraki M, Ohkawara B, Hosoya T, Onogi H, Koizumi J, Koizumi T, Sumi K, Yomoda J-i, Murray MV, Kimura H (2004) Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem 279(23):24246–24254

    Article  CAS  PubMed  Google Scholar 

  162. Nishida A, Kataoka N, Takeshima Y, Yagi M, Awano H, Ota M, Itoh K, Hagiwara M, Matsuo M (2011) Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nature Commun 2(1):1–8

    Article  Google Scholar 

  163. Sako Y, Ninomiya K, Okuno Y, Toyomoto M, Nishida A, Koike Y, Ohe K, Kii I, Yoshida S, Hashimoto N (2017) Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy. Sci Rep 7:46126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lee JY, Yun J-S, Kim W-K, Chun H-S, Jin H, Cho S, Chang JH (2019) Structural basis for the selective inhibition of Cdc2-like kinases by CX-4945. BioMed Res Int 2019:1

    CAS  Google Scholar 

  165. Tam BY, Chiu K, Chung H, Bossard C, Nguyen JD, Creger E, Eastman BW, Mak CC, Ibanez M, Ghias A (2020) The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models. Cancer Lett 473:186–197

    Article  CAS  PubMed  Google Scholar 

  166. Bates DO, Morris JC, Oltean S, Donaldson LF (2017) Pharmacology of modulators of alternative splicing. Pharmacol Rev 69(1):63–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ogawa Y, Nonaka Y, Goto T, Ohnishi E, Hiramatsu T, Kii I, Yoshida M, Ikura T, Onogi H, Shibuya H (2010) Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nature Commun 1(1):1–9

    Article  Google Scholar 

  168. Fukuhara T, Hosoya T, Shimizu S, Sumi K, Oshiro T, Yoshinaka Y, Suzuki M, Yamamoto N, Herzenberg LA, Herzenberg LA (2006) Utilization of host SR protein kinases and RNA-splicing machinery during viral replication. Proc Natl Acad Sci 103(30):11329–11333

    Article  PubMed  PubMed Central  Google Scholar 

  169. Gammons MV, Fedorov O, Ivison D, Du C, Clark T, Hopkins C, Hagiwara M, Dick AD, Cox R, Harper SJ (2013) Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Invest Ophthalmol Vis Sci 54(9):6052–6062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Chang J-G, Yang D-M, Chang W-H, Chow L-P, Chan W-L, Lin H-H, Huang H-D, Chang Y-S, Hung C-H, Yang W-K (2011) Small molecule amiloride modulates oncogenic RNA alternative splicing to devitalize human cancer cells. PLoS ONE 6(6):e18643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wang Y, Cheong C-G, Hall TMT, Wang Z (2009) Engineering splicing factors with designed specificities. Nat Methods 6(11):825–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sun S, Zhang Z, Fregoso O, Krainer AR (2012) Mechanisms of activation and repression by the alternative splicing factors RBFOX1/2. RNA 18(2):274–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Choudhury R, Tsai YS, Dominguez D, Wang Y, Wang Z (2012) Engineering RNA endonucleases with customized sequence specificities. Nat Commun 3(1):1–8

    Article  Google Scholar 

  174. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G (2014) N 6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505(7481):117–120

    Article  PubMed  Google Scholar 

  175. Du M, Jillette N, Zhu JJ, Li S, Cheng AW (2020) CRISPR artificial splicing factors. Nature. Communications 11(1):1–11

    Google Scholar 

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Acknowledgements

This work is supported by DBT/Wellcome Trust India Alliance Fellowship Grant IA/I/16/2/502719 [to S.S.]. S.N. was supported by the Department of Science and Technology, Ministry of Science and Technology. C.A. was supported by Indian Institute of Science Education and Research Bhopal.

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    Subhashis Natua, Cheemala Ashok & Sanjeev Shukla

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Natua, S., Ashok, C. & Shukla, S. Hypoxia-induced alternative splicing in human diseases: the pledge, the turn, and the prestige. Cell. Mol. Life Sci. 78, 2729–2747 (2021). https://doi.org/10.1007/s00018-020-03727-0

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