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SR Proteins and Related Factors in Alternative Splicing

  • Chapter
Alternative Splicing in the Postgenomic Era

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 623))

Abstract

SR proteins are a family of RNA binding proteins that contain a signature RS domain enriched with serine/arginine repeats. The RS domain is also found in many other proteins, which are collectively referred to as SR-related proteins. Several prototypical SR proteins are essential splicing factors, but the majority of RS domain-containing factors are characterized by their ability to alter splice site selection in vitro or in transfected cells. SR proteins and SR-related proteins are generally believed to modulate splice site selection via RNA recognition motif-mediated binding to exonic splicing enhancers and RS domain-mediated protein-protein and protein-RNA interactions during spliceosome assembly. However, the biological function of individual RS domain-containing splicing regulators is complex because of redundant as well as competitive functions, context-dependent effects and regulation by cotranscriptional and post-translational events. This chapter will focus on our current mechanistic understanding of alternative splicing regulation by SR proteins and SR-related proteins and will discuss some of the questions that remain to be addressed in future research.

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References

  1. Fu XD, Maniatis T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature 1990; 343:437–441.

    CAS  PubMed  Google Scholar 

  2. Fu XD, Maniatis T. Isolation of a complementary DNA that encodes the mammalian splicing factor SC35. Science 1992; 256:535–538.

    CAS  PubMed  Google Scholar 

  3. Ge H, Zuo F, Manley JL. Primary structure of the human splicing factor ASF reveals similarities with Drosophila regulators. Cell 1991; 66:373–382.

    CAS  PubMed  Google Scholar 

  4. Ge H, Manley JL. A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro. Cell 1990; 62:25–34.

    CAS  PubMed  Google Scholar 

  5. Krainer AR, Conway GC, Kozak D. Purification and characterization of pre-mRNA splicing factor SF2 from HeLa cells. Genes Dev 1990; 4:1158–1171.

    CAS  PubMed  Google Scholar 

  6. Krainer AR, Mayeda A, Kozak D et al. Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70K and Drosophila splicing regulators. Cell 1991; 66:383–394.

    CAS  PubMed  Google Scholar 

  7. Zahler AM, Lane WS, Stolk JA et al. SR proteins: a conserved family of pre-mRNA splicing factors. Genes Dev 1992; 6:837–847.

    CAS  PubMed  Google Scholar 

  8. Krainer AR, Conway GC, Kozak D. The essential pre-mRNA splicing factor SF2 influences 5′ splice site selection by activating proximal sites. Cell 1990; 62:35–42.

    CAS  PubMed  Google Scholar 

  9. Fu XD, Mayeda A, Maniarios T et al. General splicing factors SF2 and SC35 have equivalent activities in vitro and both affect alternative 5′ and 3′ splice site selection. Proc Natl Acad Sci USA 1992; 89:11224–11228.

    CAS  PubMed  Google Scholar 

  10. Zahler AM, Neugebauer KM, Lane WS et al. Distinct functions of SR proteins in alternative pre-mRNA splicing. Science 1993; 260:219–222.

    CAS  PubMed  Google Scholar 

  11. Cavaloc Y, Popielarz M, Fuchs JP et al. Characterization and cloning of the human splicing factor 9G8: a novel 35 kDa factor of the serine/arginine proton family. EMBO J 1994; 13:2639–2649.

    CAS  PubMed  Google Scholar 

  12. Fu XD. The superfamily of arginine/serine-rich splicing factors. RNA 1995; 1:663–680.

    CAS  PubMed  Google Scholar 

  13. Graveley BR. Sorting out the complexity of SR protein fonctions. RNA 2000; 6:1197–1211.

    CAS  PubMed  Google Scholar 

  14. Boucher L, Ouzounis CA, Enright AJ et al. A genome-wide survey of RS domain proteins. RNA 2001; 7:1693–1701.

    CAS  PubMed  Google Scholar 

  15. Ono Y, Ohno M, Shimura Y. Identification of a putative RNA helicase (HRH1), a human homolog of yeast Prp22. Mol Cell Biol 1994; 14:7611–7620.

    CAS  PubMed  Google Scholar 

  16. Teigelkamp S, Mundt C, Achsel T et al. The human U5 snRNP-specific 100-kD protein is an RS domain-containing, putative RNA helicase with significant homology to the yeast splicing factor Prp28p. RNA 1997; 3:1313–1326.

    CAS  PubMed  Google Scholar 

  17. Ortlepp D, Laggerbauer B, Mullner S et al. The mammalian homologue of Prp16p is overexpressed in a cell Une tolerant to Leflunomide, a new immunoregulatory drug effective against rheumatoid arthritis. RNA 1998; 4:1007–1018.

    CAS  PubMed  Google Scholar 

  18. Sukegawa J, Blobel G. A putative mammalian RNA helicase with an argininc-serine-rich domain colocalizes with a splicing factor. J Biol Chem 1995; 270:15702–15706.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Shen H, Green MR. A pathway of sequential arginine-serine-rich domain-splicing signal interactions during mammalian spliceosome assembly. Mol Cell 2004; 16:363–373.

    CAS  PubMed  Google Scholar 

  21. Shen H, Kan JL, Green MR. Arginine-serine-rich domains bound at splicing enhancers contact the branchpoint to promote prespliceosome assembly. Mol Cell 2004; 13:367–376.

    CAS  PubMed  Google Scholar 

  22. Birney E, Kumar S, Krainer AR. Analysis of the RNA-recognition motif and RS and RGG domains: conservation in metazoan pre-mRNA splicing factors. Nucleic Acids Res 1993; 21:5803–5816.

    CAS  PubMed  Google Scholar 

  23. Shen H, Green MR. RS domains contact splicing signals and promote splicing by a common mechanism in yeast through humans. Genes Dev 2006; 20:1755–1765.

    CAS  PubMed  Google Scholar 

  24. Cavaloc Y, Bourgeois CF, Kister L et al. The splicing factors 9G8 and SRp20 transactivate splicing through different and specific enhancers. RNA 1999; 5:468–483.

    CAS  PubMed  Google Scholar 

  25. Tacke R, Manley JL. The human splicing factors ASF/SF2 and SC35 possess distinct, functionally significant RNA binding specificities. EMBO J 1995; 14:3540–3551.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Liu HX, Chew SL, Cartegni L et al. Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol Cell Biol 2000; 20:1063–1071.

    CAS  PubMed  Google Scholar 

  28. Schaal TD, Maniatis T. Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences. Mol Cell Biol 1999; 19:1705–1719.

    CAS  PubMed  Google Scholar 

  29. Cartegni L, Wang J, Zhu Z et al. ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res 2003; 31:3568–3571.

    CAS  PubMed  Google Scholar 

  30. Lynch KW, Maniatis T. Assembly of specific SR protein complexes on distinct regulatory elements of the Drosophila doublesex splicing enhancer. Genes Dev 1996; 10:2089–2101.

    CAS  PubMed  Google Scholar 

  31. Lynch KW, Maniatis T. Synergistic interactions between two distinct elements of a regulated splicing enhancer. Genes Dev 1995; 9:284–293.

    CAS  PubMed  Google Scholar 

  32. Wang Z, Rolish ME, Yeo G et al. Systematic identification and analysis of exonic splicing silencers. Cell 2004; 119:831–845.

    CAS  PubMed  Google Scholar 

  33. Fairbrother WG, Yeh RF, Sharp PA et al Predictive identification of exonic splicing enhancers in human genes. Science 2002; 297:1007–1013.

    CAS  PubMed  Google Scholar 

  34. Fairbrother WG, Yeo GW, Yeh R et al. RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res 2004; 32:W187–W190.

    CAS  PubMed  Google Scholar 

  35. Zhang XH, Leslie CS, Chasin LA. Computational searches for splicing signals. Methods 2005; 37:292–305.

    CAS  PubMed  Google Scholar 

  36. Zhang XH, Chasin LA. Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev 2004; 18:1241–1250.

    CAS  PubMed  Google Scholar 

  37. Zahler AM, Roth MB. Distinct functions of SR proteins in recruitment of U1 small nuclear ribonucleoprotein to alternative 5′ splice sites. Proc Natl Acad Sci USA 1995; 92:2642–2646.

    CAS  PubMed  Google Scholar 

  38. Kohtz JD, Jamison SF, Will CL et al. Protein-protein interactions and 5′-splice-site recognition in mammalian mRNA precursors. Nature 1994; 368:119–124.

    CAS  PubMed  Google Scholar 

  39. Zuo P, Manley JL. The human splicing factor ASF/SF2 can specifically recognize pre-mRNA 5′ splice sites. Proc Natl Acad Sci USA 1994; 91:3363–3367.

    CAS  PubMed  Google Scholar 

  40. Wang Z, Hoffmann HM, Grabowski PJ. Intrinsic U2AF binding is modulated by exon enhancer signals in parallel with changes in splicing activity. RNA 1995; 1:21–35.

    CAS  PubMed  Google Scholar 

  41. Li Y, Blencowe BJ. Distinct factor requirements for exonic splicing enhancer function and binding of U2AF to the polypyrimidine tract. J Biol Chem 1999; 274:35074–35079.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Zuo P, Maniatis T. The splicing factor U2AF35 mediates critical protein-protein interactions in constitutive and enhancer-dependent splicing. Genes Dev 1996; 10:1356–1368.

    CAS  PubMed  Google Scholar 

  44. Hertel KJ, Maniatis T. Serine-arginine (SR)-rich splicing factors have an exon-independent function in pre-mRNA splicing. Proc Natl Acad Sci USA 1999; 96:2651–2655.

    CAS  PubMed  Google Scholar 

  45. Boukis LA, Liu N, Furuyama S et al. Ser/Arg-rich protein-mediated communication between U1 and U2 small nuclear ribonucleoprotein particles. J Biol Chem 2004; 279:29647–29653.

    CAS  PubMed  Google Scholar 

  46. Fu XD, Maniatis T. The 35-kDa mammalian splicing factor SC35 mediates specific interactions between U1 and U2 small nuclear ribonucleoprotein particles at the 3′ splice site. Proc Natl Acad Sci USA 1992; 89:1725–1729.

    CAS  PubMed  Google Scholar 

  47. Stark JM, Bazett-Jones DP, Herfort M et al. SR proteins are sufficient for exon bridging across an intron. Proc Natl Acad Sci U S A 1998; 95:2163–2168.

    CAS  PubMed  Google Scholar 

  48. Blencowe BJ, Issner R, Nickerson JA et al. A coactvator of pre-mRNA splicing. Gene & Dev. 1998; 12:996–1009.

    CAS  Google Scholar 

  49. Blencowe BJ, Bauren G, Eldridge G et al. The SRm 160/300 splicing coactivator subunites. RNA 200; 6:111–120.

    Google Scholar 

  50. Zhu J, Mayeda A, Krainer AR. Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Mol Cell 2001; 8:1351–1361.

    CAS  PubMed  Google Scholar 

  51. Kan JL, Green MR. Pre-mRNA splicing of IgM exons M1 and M2 is directed by a juxtaposed splicing enhancer and inhibitor. Genes Dev 1999; 13:462–471.

    CAS  PubMed  Google Scholar 

  52. Reed R, Maniatis T. A role for exon sequences and splice-site proximity in splice-site selection. Cell 1986; 46:681–690.

    CAS  PubMed  Google Scholar 

  53. Mayeda A, Krainer AR. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 1992; 68:365–375.

    CAS  PubMed  Google Scholar 

  54. Wang Z, Xiao X, Van Nostrand E et al. General and specific functions of exonic splicing silencers in splicing control. Mol Cell 2006; 23:61–70.

    CAS  PubMed  Google Scholar 

  55. Eperon IC, Makarova OV, Mayeda A et al. Selection of alternative 5′ splice sites: role of U1 snRNP and models for the antagonistic effects of SF2/ASF and hnRNP A1. Mol Cell Biol 2000; 20:8303–8318.

    CAS  PubMed  Google Scholar 

  56. Ibrahim el C, Schaal TD, Hertel KJ et al. Serine/arginine-rich protein-dependent suppression of exon skipping by exonic splicing enhancers. Proc Natl Acad Sci USA 2005; 102:5002–5007.

    CAS  PubMed  Google Scholar 

  57. Chandler SD, Mayeda A, Yeakley JM et al. RNA splicing specificity determined by the coordinated action of RNA recognition motifs in SR proteins. Proc Natl Acad Sci USA 1997; 94:3596–3601.

    CAS  PubMed  Google Scholar 

  58. Caceres JF, Krainer AR. Functional analysis of pre-mRNA splicing factor SF2/ASF structural domains. EMBO J 1993; 12:4715–4726.

    CAS  PubMed  Google Scholar 

  59. Zuo P, Manley JL. Functional domains of the human splicing factor ASF/SF2. EMBO J 1993; 12:4727–4737.

    CAS  PubMed  Google Scholar 

  60. Zhu J, Krainer AR. Pre-mRNA splicing in the absence of an SR protein RS domain. Genes Dev 2000; 14:3166–3178.

    CAS  PubMed  Google Scholar 

  61. Kanopka A, Muhlemann O, Akusjarvi G. Inhibition by SR proteins of splicing of a regulated adenovirus pte-mRNA. Nature 1996; 381:535–538.

    CAS  PubMed  Google Scholar 

  62. Xu X, Yang D, Ding JH et al. ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell 2005; 120:59–72.

    CAS  PubMed  Google Scholar 

  63. Ghigna C, Giordano S, Shen H et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 2005; 20:881–890.

    CAS  PubMed  Google Scholar 

  64. Simard MJ, Chabot B. SRp30c is a repressor of 3′ splice site utilization. Mol Cell Biol 2002; 22:4001–4010.

    CAS  PubMed  Google Scholar 

  65. Gallego ME, Gattoni R, Stevenin J et al. The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the beta-tropomyosin alternative exon 6A. EMBO J 1997; 16:1772–1784.

    CAS  PubMed  Google Scholar 

  66. Jumaa H, Nielsen PJ. The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J 1997; 16:5077–5085.

    CAS  PubMed  Google Scholar 

  67. Lemaire R, Winne A, Sarkissian M et al. SF2 and SRp55 regulation of CD45 exon 4 skipping during T-cell activation. Ear J Immunol 1999; 29:823–837.

    CAS  Google Scholar 

  68. ten Dam GB, Zilch CF, Wallace D et al. Regulation of alternative splicing of CD45 by antagonistic effects of SR protein splicing factors. J Immunol 2000; 164:5287–5295.

    PubMed  Google Scholar 

  69. Watermann DO, Tang Y, Zur Hausen A et al. Splicing factor Tra2-betal is specifically induced in breast cancer and regulates alternative splicing of the CD44 gene. Cancer Res 2006; 66:4774–4780.

    CAS  PubMed  Google Scholar 

  70. Goren A, Ram O, Amit M et al. Comparative analysis identifies exonic splicing regulatory sequences— The complex definition of enhancers and silencers. Mol Cell 2006; 22:769–781.

    CAS  PubMed  Google Scholar 

  71. Barnard DC, Li J, Peng R et al. Regulation of alternative splicing by SRrp86 through coactivation and repression of specific SR proteins. RNA 2002; 8:526–533.

    CAS  PubMed  Google Scholar 

  72. Li J, Barnard DC, Pattern JG. A unique glutamic acid-lysine (EK) domain acts as a splicing inhibitor. J Biol Chem 2002; 277:39485–39492.

    CAS  PubMed  Google Scholar 

  73. Li J, Hawkins IC, Harvey CD et al. Regulation of alternative splicing by SRrp86 and its interacting proteins. Mol Cell Biol 2003; 23:7437–7447.

    CAS  PubMed  Google Scholar 

  74. Zhang WJ. Wu JY. Functional properties of p54 a novel SR protein active in constitutive and alternative splicing. Mol Cell Biol 1996; 16:5400–5408.

    CAS  PubMed  Google Scholar 

  75. Wu JY, Kar A, Kuo D et al. SRp54 (SFRS11), a regualtor for tau exon 10 alternative splicing identified by an expression cloning strategy. Mol Cell Biol 2006; 26:6739–6747.

    CAS  PubMed  Google Scholar 

  76. Cowper AE, Caceres JF, Mayeda A et al. Serine-arginine (SR) protein-like factors that antagonize authentic SR proteins and regulate alternative splicing. J Biol Chem 2001; 276:48908–48914.

    CAS  PubMed  Google Scholar 

  77. Yang L, Embree LJ, Hickstein DD. TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins. Mol Cell Biol 2000; 20:3345–3354

    CAS  PubMed  Google Scholar 

  78. Komatsu M, Kominami E, Arahata K et al. Cloning and characterization of two neural-salient serine/ arginine-rich (NSSR) proteins involved in the regulation of alternative splicing in neurones. Genes Cells 1999; 4:593–606.

    CAS  PubMed  Google Scholar 

  79. Fushimi K, Osumi N, Tsukahara T. NSSRs/TASRs/SRp38s function as splicing modulators via binding to pre-mRNAs. Genes Cells 2005; 10:531–541.

    CAS  PubMed  Google Scholar 

  80. Shin C, Manley JL. The SR protein SRp38 represses splicing in M phase cells. Cell 2002; 111:407–417.

    CAS  PubMed  Google Scholar 

  81. Shin C, Feng Y, Manley JL. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 2004; 427:553–558.

    CAS  PubMed  Google Scholar 

  82. Shin C, Kleiman FE, Manley JL. Multiple properties of the splicing repressor SRp38 distinguish it from typical SR proteins. Mol Cell Biol 2005; 25:8334–8343.

    CAS  PubMed  Google Scholar 

  83. Tacke R, Tohyama M, Ogawa S et al. Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing. Cell 1998; 93:139–148.

    CAS  PubMed  Google Scholar 

  84. Pacheco TR, Moita LF, Gomes AQ et al. RNAi Knockdown of hU2AF35 Impairs Cell Cycle Progression and Modulates Alternative Splicing of Cdc25 Transcripts. Mol Biol Cell 2006.

    Google Scholar 

  85. Park JW, Parisky K, Celotto AM et al. Identification of alternative splicing regulators by RNA interference in Drosophila. Proc Natl Acad Sci USA 2004; 101:15974–15979.

    CAS  PubMed  Google Scholar 

  86. Valcarcel J, Singh R, Zamore PD et al. The protein Sex-lethal antagonizes the splicing factor U2AF to regulate alternative splicing of transformer pre-mRNA. Nature 1993; 362:171–175.

    CAS  PubMed  Google Scholar 

  87. Lou H, Helfman DM, Gagel RF et al. Polypyrimidine tract-binding protein positively regulates inclusion of an alternative 3′-terminal exon. Mol Cell Biol 1999; 19:78–85.

    CAS  PubMed  Google Scholar 

  88. Izquierdo JM, Majos N, Bonnal S et al. Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on earn definition. Mol Cell 2005; 19:475–484.

    CAS  PubMed  Google Scholar 

  89. Sharma S, Falick AM, Black DL. Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex. Mol Cell 2005; 19:485–496.

    CAS  PubMed  Google Scholar 

  90. Sarkissian M, Winne A, Lafyatis R. The mammalian homolog of suppressor-of-white-apricot regulates alternative mRNA splicing of CD45 exon 4 and fibronectin IIICS. J Biol Chem 1996; 271:31106–31114.

    CAS  PubMed  Google Scholar 

  91. Adams DJ, van der Weyden L, Mayeda A et al. ZNF265—a novel spliceosomal protein able to induce alternative splicing. J Cell Biol 2001; 154:25–32.

    CAS  PubMed  Google Scholar 

  92. Prasad J, Colwill K, Pawson T et al. The protein kinase Clk/Sty directly modulates SR protein activity: both hyperand hypophosphorylation inhibit splicing. Mol Cell Biol 1999; 19:6991–7000.

    CAS  PubMed  Google Scholar 

  93. Colwill K, Pawson T andrews B et al. The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. EMBO J 1996; 15:265–275.

    CAS  PubMed  Google Scholar 

  94. Ko TK, Kelly E, Fines J. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci 2001; 114:2591–2603.

    CAS  PubMed  Google Scholar 

  95. Dellaire G, Makarov EM, Cowger JJ et al. Mammalian PRP4 kinase copurifies and interacts with components of both the U5 snRNP and the N-CoR deacetylase complexes. Mol Cell Biol 2002; 22:5141–5156.

    CAS  PubMed  Google Scholar 

  96. Even Y, Durieux S, Escande ML et al. CDC2L5, a Cdk-like kinase with RS domain, interacts with the ASF/SF2-associated protein p32 and affects splicing in vivo. J Cell Biochem 2006.

    Google Scholar 

  97. Dickinson LA, Edgar AJ, Ehley J et al. Cyclin L is an RS domain protein involved in pre-mRNA splicing. J Biol Chem 2002; 277:25465–25473.

    CAS  PubMed  Google Scholar 

  98. Chen HH, Wang YC, Fann MJ. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol Cell Biol 2006; 26:2736–2745.

    CAS  PubMed  Google Scholar 

  99. Yang L, Li N, Wang C et al. Cyclin L2, a novel RNA polymerase II-associated cyclin, is involved in pre-mRNA splicing and induces apoptosis of human hepatocellular carcinoma cells. J Biol Chem 2004; 279:11639–11648.

    CAS  PubMed  Google Scholar 

  100. de Graaf K, Hekerman P, Spelten O et al. Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors, J Biol Chem 2004; 279:4612–4624.

    PubMed  Google Scholar 

  101. Lim SR, Hertel KJ. Commitment to splice site pairing coincides with A complex formation. Mol Cell 2004; 15:477–483.

    CAS  PubMed  Google Scholar 

  102. Query CC, Konarska MM. Suppression of multiple substrate mutations by spliceosomal prp8 alleles suggests functional correlations with ribosomal ambiguity mutants. Mol Cell 2004; 14:343–354.

    CAS  PubMed  Google Scholar 

  103. Longman D, Johnstone IL, Caceres JE Functional characterization of SR and SR-related genes in Caenorhabditis elegans. EMBO J 2000; 19:1625–1637.

    CAS  PubMed  Google Scholar 

  104. Gabut M, Mine M, Marsac C et al. The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Mol Cell Biol 2005; 25:3286–3294.

    CAS  PubMed  Google Scholar 

  105. Massiello A, Chalfant CE. SRp30a (ASF/SF2) regulates the alternative splicing of caspase-9 pre-mRNA and is required for ceramide-responsiveness. J Lipid Res 2006; 47:892–897.

    CAS  PubMed  Google Scholar 

  106. Wang J, Xiao SH, Manley JL. Genetic analysis of the SR protein ASF/SF2: interchangeability of RS domains and negative control of splicing. Genes Dev 1998; 12:2222–2233.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  108. Li X, Wang J, Manley JL. Loss of splicing factor ASF/SF2 induces G2 cell cycle arrest and apoptosis, but inhibits internucleosomal DNA fragmentation. Genes Dev 2005; 19:2705–2714.

    CAS  PubMed  Google Scholar 

  109. Wang HY, Xu X, Ding JH et al. SC35 plays a role in T-cell development and alternative splicing of CD45. Mol Cell 2001; 7:331–342.

    CAS  PubMed  Google Scholar 

  110. Jumaa H, Wei G, Nielsen PJ. Blastocyst formation is blocked in mouse embryos lacking the splicing factor SRp20. Curr Biol 1999; 9:899–902.

    CAS  PubMed  Google Scholar 

  111. Ding JH, Xu X, Yang D et al. Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart. EMBO J 2004; 23:885–896.

    CAS  PubMed  Google Scholar 

  112. Lin S, Xiao R, Sun P et al. Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation. Mol Cell 2005; 20:413–425.

    CAS  PubMed  Google Scholar 

  113. Allemand E, Gattoni R, Bourbon HM et al. Distinctive features of Drosophila alternative splicing factor RS domain: implication for specific phosphorylation, shuttling and splicing activation. Mol Cell Biol 2001; 21:1345–1359.

    CAS  PubMed  Google Scholar 

  114. Lemaire R, Prasad J, Kashima T et al. Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins. Genes Dev 2002; 16:594–607.

    CAS  PubMed  Google Scholar 

  115. Venables JP, Bourgeois CF, Dalgliesh C et al. Up-regulation of the ubiquitous alternative splicing factor Tra2beta causes inclusion of a germ cell-specific exon. Hum Mol Genet 2005; 14:2289–2303.

    CAS  PubMed  Google Scholar 

  116. Schaal TD, Maniatis T. Multiple distinct splicing enhancers in the protein-coding sequences of a constitutively spliced pre-mRNA. Mol Cell Biol 1999; 19:261–273.

    CAS  PubMed  Google Scholar 

  117. Hertel KJ, Maniatis T. The function of multisite splicing enhancers. Mol Cell 1998; 1:449–455.

    CAS  PubMed  Google Scholar 

  118. Hanamura A, Caccres JF, Mayeda A et al. Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors. RNA 1998; 4:430–444.

    CAS  PubMed  Google Scholar 

  119. Du K, Leu JI, Peng Y et al. Transcriptional up-rcgulation of the delayed early gene HRS/SRp40 during liver regeneration. Interactions among YY1, GA-binding proteins and mitogenic signals. J Biol Chem 1998; 273:35208–35215.

    CAS  PubMed  Google Scholar 

  120. Shinozaki A, Arahata K, Tsukahara T. Changes in pre-mRNA splicing factors during neural differentiation in P19 embryonal carcinoma cells. Int J Biochem Cell Biol 1999; 31:1279–1287.

    CAS  PubMed  Google Scholar 

  121. Jumaa H, Guenet JL, Nielsen PJ. Regulated expression and RNA processing of transcripts from the Srp20 splicing factor gene during the cell cycle. Mol Cell Biol 1997; 17:3116–3124.

    CAS  PubMed  Google Scholar 

  122. Chiu Y, Ouyang P. Loss of Pnn expression attenuates expression levels of SR family splicing factors and modulates alternative pre-mRNA splicing in vivo. Biochem Biophys Res Commun 2006; 341:663–671.

    CAS  PubMed  Google Scholar 

  123. Jumaa H, Nielsen PJ. Regulation of SRp20 earn 4 splicing. Biochim Biophys Acta 2000; 1494:137–143.

    CAS  PubMed  Google Scholar 

  124. Lejeune F, Cavaloc Y, Stevenin J. Alternative splicing of intron 3 of the serine/arginine-rich protein 9G8 gene. Identification of flanking exonic splicing enhancers and involvement of 9G8 as a trans-acting factor. J Biol Chem 2001; 276:7850–7858.

    CAS  PubMed  Google Scholar 

  125. Sureau A, Gattoni R, Dooghe Y et al. SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs. EMBO J 2001; 20:1785–1796.

    CAS  PubMed  Google Scholar 

  126. Stoilov F, Daoud R, Nayler O et al. Human tra2-betal autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA. Hum Mol Genet 2004; 13:509–524.

    CAS  PubMed  Google Scholar 

  127. Mermoud JE, Cohen P, Lamond AI. Ser/Thr-specific protein phosphatases are required for both catalytic steps of pre-mRNA splicing. Nucleic Acids Res 1992; 20:5263–5269.

    CAS  PubMed  Google Scholar 

  128. Mermoud JE, Cohen PT, Lamond AL Regulation of mammalian spliceosome assembly by a protein phosphorylation mechanism. EMBO J 1994; 13:5679–5688.

    CAS  PubMed  Google Scholar 

  129. Xiao SH, Manley JL. Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO J 1998; 17:6359–6367.

    CAS  PubMed  Google Scholar 

  130. Cao W, Jamison SF, Garcia-Blanco MA. Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro. RNA 1997: 3:1456–1467.

    CAS  PubMed  Google Scholar 

  131. Cazalla D, Zhu J, Manche L et al. Nuclear export and retention signals in the RS domain or SR proteins. Mol Cell Biol 2002; 22:6871–6882.

    CAS  PubMed  Google Scholar 

  132. Hartmann AM, Rujescu D, Giannakouros T et al. Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol Cell Neurosci 2001; 18:80–90.

    CAS  PubMed  Google Scholar 

  133. Muraki M, Ohkawara B, Hosoya T et al. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem 2004; 279:24246–24254.

    CAS  PubMed  Google Scholar 

  134. Duncan PL Stojdl DF, Marius RM et al. In vivo regulation of alternative pre-mRNA splicing by the Clk1 protein Kinase. Mol Cell Biol 1997; 17:5996–6001.

    CAS  PubMed  Google Scholar 

  135. Cardinali B, Cohen PT, Lamond AI. Protein phosphatase 1 can modulate alternative 5′ splice site selection in a HeLa splicing extract. FEBS Lett 1994; 352:276–280.

    CAS  PubMed  Google Scholar 

  136. Blaustein M, Pelisch F, Tanas T et al. Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nat Struct Mol Biol 2005; 12:1037–1044.

    CAS  PubMed  Google Scholar 

  137. Patel NA, Kaneko S, Apostolatos HS et al. Molecular and genetic studies imply Akr-mediated signaling promotes protein Kinase CbetaII alternative splicing via phosphorylation of serine/arginine-rich splicing factor SRp.40 J Biol Chem 2005; 280:14302–14309.

    CAS  PubMed  Google Scholar 

  138. Xiao SH, Manley JL. Phosphorylation of the ASF/SE2 RS domain affects both protein-protein and protein-RNA interactions and is necessary for splicing. Genes Dev 1997; 11:334–344.

    CAS  PubMed  Google Scholar 

  139. Yeakley JM, Tronchere H, Olesen J et al. Phosphorylation regulates in vivo interaction and molecular targeting of serine/arginine-rich pre-mRNA splicing factors. J Cell Biol 1999; 145:447–455.

    CAS  PubMed  Google Scholar 

  140. Velazquez-Dones A, Hagopian JC, Ma CT et al. Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty. J Biol Chem 2005; 280:41761–41768.

    CAS  PubMed  Google Scholar 

  141. Gui JF, Lane WS, Fu XD. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature 1994; 369:678–682.

    CAS  PubMed  Google Scholar 

  142. Koizumi J, Okamoto Y, Onogi H et al. The subcellular localization of SF2/ASF is regulated by direct interaction with SR protein kinases (SRPKs). J Biol Chem 1999; 274:11125–11131.

    CAS  PubMed  Google Scholar 

  143. Wang HY, Lin W, Dyck JA et al. SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J Cell Biol 1998; 140:737–750.

    CAS  PubMed  Google Scholar 

  144. Misteli T, Caceres JF, Clement JQ et al. Serine phosphorylation of SR proteins is required for their recruitment to sites of transcription in vivo. J Cell Biol 1998; 143:297–307.

    CAS  PubMed  Google Scholar 

  145. Misteli T, Spector DL. RNA polymerase II targets pre-mRNA splicing factors to transcription sites in vivo. Mol Cell 1999; 3:697–705.

    CAS  PubMed  Google Scholar 

  146. Colwill K, Feng LL, Yeakley JM et al. SRPK1 and Clk/Sty protein kinascs show distinct substrate specificities for serine/arginine-rich splicing factors. J Biol Chan 1996; 271:24569–24575.

    CAS  Google Scholar 

  147. Da C, McGuffin ME, Dauwalder B et al. Protein phosphorylation plays an essential role in the regulation of alternative splicing and sex determination in Drosophila. Mol Cell 1998; 2:741–750.

    Google Scholar 

  148. Gui JF, Tronchere H, Chandler SD et al. Purification and characterization of a kinase specific for the serine-and arginine-rich pre-mRNA splicing factors. Proc Natl Acad Sci USA 1994; 91:10824–10828.

    CAS  PubMed  Google Scholar 

  149. Hayes GM, Carrigan PE, Beck AM et al. Targeting the RNA splicing machinery as a novel treatment strategy for pancreatic carcinoma. Cancer Res 2006; 66:3819–3827.

    CAS  PubMed  Google Scholar 

  150. Kanopka A, Muhlemann O, Petersen-Mahrt S et al. Regulation of adenovirus alternative RNA splicing by dephosphorylation of SR proteins. Nature 1998; 393:185–187.

    CAS  PubMed  Google Scholar 

  151. Misteli T, Spector DL. Serine/threonine phosphatase 1 modulates the subnuclear distribution of pre-mRNA splicing factors. Mol Biol Cell 1996; 7:1559–1572.

    CAS  PubMed  Google Scholar 

  152. Tran HT, Ulke A, Morrice N et al. Proteomic characterization of protein phosphatase complexes of the mammalian nucleus. Mol Cell Proteomics 2004; 3:257–265.

    CAS  PubMed  Google Scholar 

  153. Shi Y, Reddy B, Manley JL. PP1/PP2A phospharases are required for the second step of Pre-mRNA splicing and target specific snRNP proteins. Mol Cell 2006; 23:819–829.

    CAS  PubMed  Google Scholar 

  154. Siebel CW, Feng L, Guthrie C et al. Conservation in budding yeast of a kinase specific for SR splicing factors. Proc Natl Acad Sci USA 1999; 96:5440–5445.

    CAS  PubMed  Google Scholar 

  155. Gilbert W, Guthrie C. The Glc7p nuclear phosphatase promotes mRNA export by facilitating association of Mex67p with mRNA. Mol Cell 2004; 13:201–212.

    CAS  PubMed  Google Scholar 

  156. Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev 2003; 17:419–437.

    CAS  PubMed  Google Scholar 

  157. Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 2002; 3:285–298.

    CAS  PubMed  Google Scholar 

  158. Colapietro P, Gervasini C, Natacci F et al. NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient. Hum Genet 2003; 113:551–554.

    CAS  PubMed  Google Scholar 

  159. Guil S, Gattoni R, Carrascal M et al. Roles of hnRNP A1, SR proteins and p68 helicase in c-H-ras alternative splicing regulation. Mol Cell Biol 2003; 23:2927–2941.

    CAS  PubMed  Google Scholar 

  160. Ghigna C, Moroni M, Porta C et al. Altered expression of heterogenous nuclear ribonucleoproteins and SR factors in human colon adenocarcinomas. Cancer Res 1998; 58:5818–5824.

    CAS  PubMed  Google Scholar 

  161. Stickeler E, Kittrell F, Medina D et al. Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogens 1999; 18:3574–3582.

    CAS  Google Scholar 

  162. Maeda T, Furukawa S. Transformation-associated changes in gene expression of alternative splicing regulatory factors in mouse fibroblast cells. Oncol Rep 2001; 8:563–566.

    CAS  PubMed  Google Scholar 

  163. Fischer DC, Noack K, Runnebaum IB et al. Expression of splicing factors in human ovarian cancer. Oncol Rep 2004; 11:1085–1090.

    CAS  PubMed  Google Scholar 

  164. Zerbe LK, Pino I, Pio R et al. Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/ SF2, change during neoplastic lung growth: implications for pre-mRNA processing. Mol Carcinog 2004; 41:187–196.

    CAS  PubMed  Google Scholar 

  165. Pind MT, Watson PH. SR protein expression and CD44 splicing pattern in human breast tumours. Breast Cancer Res Treat 2003; 79:75–82.

    CAS  PubMed  Google Scholar 

  166. Lorson CL, Hahnen E androphy EJ et al. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999; 96:6307–6311.

    CAS  PubMed  Google Scholar 

  167. Cartegni L, Hastings ML, Calarco JA et al. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet 2006; 78:63–77.

    CAS  PubMed  Google Scholar 

  168. Kashima T, Manley JL. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy, Nat Genet 2003; 34:460–463.

    CAS  PubMed  Google Scholar 

  169. Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet 2002; 30:377–384.

    CAS  PubMed  Google Scholar 

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  1. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA

    Shengrong Lin & Xiang-Dong Fu

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  1. Shengrong Lin
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  1. Banting and Best Department of Medical Research and Department of Molecular and Medical Genetics, Terrence Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto, Canada

    Benjamin J. Blencowe Ph.D.

  2. Department of Genetics and Development Biology, University of Connecticut Health Center, Farmington, Connecticut, USA

    Brenton R. Graveley Ph.D.

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Lin, S., Fu, XD. (2007). SR Proteins and Related Factors in Alternative Splicing. In: Blencowe, B.J., Graveley, B.R. (eds) Alternative Splicing in the Postgenomic Era. Advances in Experimental Medicine and Biology, vol 623. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77374-2_7

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  • DOI: https://doi.org/10.1007/978-0-387-77374-2_7

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