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  • Review Article
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Cell signalling and the control of pre-mRNA splicing

Nature Reviews Molecular Cell Biology volume 5, pages 727–738 (2004)Cite this article

Key Points

  • Unlike transcription, where regulation is initiated most frequently by high-affinity, sequence-specific DNA-binding proteins, splicing regulation is frequently brought about by cooperative interactions between factors such as serine-arginine rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), which have lower affinities and sequence specificities.

  • HnRNP A1 represses variant exon-5 (v5) inclusion in human CD44 pre-mRNA in most tissues. In T cells that are activated by Ras signalling, SAM68, which is phosphorylated by extracellular signal-regulated kinase (ERK), interacts with v5 RNA in a way that interferes with the repressive activity of hnRNP A1, and enhances v5 inclusion in the final CD44 mRNA.

  • Fas-mediated signalling regulates the alternative splicing of transcripts that encode apoptotic regulators. Alterations in the phosphorylation status of SR proteins probably lead to changes in alternative splicing of BCL-X pre-mRNAs. Additionally, Fas-mediated phosphorylation of TIA1 might modulate the alternative splicing of Fas pre-mRNA, thereby providing a positive autoregulatory loop to enhance Fas signalling.

  • SRp38 functions as a splicing repressor when it is activated by dephosphorylation during M phase of the cell cycle and in response to heat shock. Splicing inhibition is brought about by an interaction between dephosphorylated SRp38, U1 small nuclear ribonucleoprotein particles (U1 snRNPs), and possibly other snRNPs.

  • Ania-6–cyclin-dependent-kinasep100 (CDK11p100) provides a link between dopamine signalling and transcription-coupled splicing by phosphorylating SR proteins and the carboxy-terminal domain of the largest subunit of RNA polymerase II (RNAPII CTD).

  • After depolarization of GH3 pituitary cells, the inclusion of the stress-axis-regulated (STREX) exon of the SLO pre-mRNA is repressed by the CaRRE (Ca2+/calmodulin-dependent protein kinase (CaMK)IV-responsive RNA element)-specific binding of an unidentified protein that is phosphorylated by CaMKIV.

Abstract

The transcripts of most metazoan protein-coding genes are alternatively spliced, but the mechanisms that are involved in the control of splicing are not well understood. Recent evidence supports the potential of both extra- and intracellular signalling to the splicing machinery as a means of regulating gene expression, and indicates that this form of gene control is widespread and mechanistically complex. However, important questions about these pathways need to be answered before this method of post-transcriptional regulation can be fully appreciated.

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Figure 1: Regulation of variant exon-5 (v5) splicing in human CD44 pre-mRNA.
Figure 2: Fas-mediated signalling regulates the alternative splicing of transcripts that encode apoptotic regulators.
Figure 3: Splicing repression by dSRp38 during M phase or in response to heat shock.
Figure 4: Interaction between Ania-6 and CDK11p110 provides a link between dopamine signalling and transcription-coupled splicing.
Figure 5: Alternative splicing regulation of the STREX exon of the SLO pre-mRNA.

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References

  1. Mironov, A. A., Fickett, J. W. & Gelfand, M. S. Frequent alternative splicing of human genes. Genome Res. 9, 1288–1293 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Kan, Z., Rouchka, E. C., Gish, W. R. & States, D. J. Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res. 11, 889–900 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Modrek, B., Resch, A., Grasso, C. & Lee, C. Genome-wide analysis of alternative splicing using human expressed sequence data. Nucleic Acids Res. 29, 2850–2859 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blencowe, B. J. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem. Sci. 25, 106–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Smith, C. W. & Valcarcel, J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem. Sci. 25, 381–388 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Grabowski, P. J. & Black, D. L. Alternative RNA splicing in the nervous system. Prog. Neurobiol. 65, 289–308 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Graveley, B. R. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 17, 100–107 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Maniatis, T. & Tasic, B. Alternative pre-mRNA splicing and proteome expansion in metazoans. Nature 418, 236–243 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Black, D. L. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72, 291–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Manley, J. L. & Tacke, R. SR proteins and splicing control. Genes Dev. 10, 1569–1579 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Graveley, B. R. Sorting out the complexity of SR protein functions. RNA 6, 1197–1211 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu, J. Y. & Maniatis, T. Specific interactions between proteins implicated in splice site selection and regulated alternative splicing. Cell 75, 1061–1070 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Kohtz, J. D. et al. Protein–protein interactions and 5′-splice-site recognition in mammalian mRNA precursors. Nature 368, 119–124 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Xiao, S. H. & Manley, J. L. Phosphorylation of the ASF/SF2 RS domain affects both protein–protein and protein–RNA interactions and is necessary for splicing. Genes Dev. 11, 334–344 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Xiao, S. H. & Manley, J. L. Phosphorylation–dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO J. 17, 6359–6367 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gui, J. F., Lane, W. S. & Fu, X. D. A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature 369, 678–682 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Colwill, K. et al. The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. EMBO J. 15, 265–275 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Duncan, P. I. et al. Alternative splicing of STY, a nuclear dual specificity kinase. J. Biol. Chem. 270, 21524–21531 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, K., Du, C., Horn, M. & Rabinow, L. Activity and autophosphorylation of LAMMER protein kinases. J. Biol. Chem. 271, 27299–27303 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Nayler, O., Stamm, S. & Ullrich, A. Characterization and comparison of four serine- and arginine-rich (SR) protein kinases. Biochem. J. 326, 693–700 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prasad, J., Colwill, K., Pawson, T. & Manley, J. L. The protein kinase Clk/Sty directly modulates SR protein activity: both hyper- and hypophosphorylation inhibit splicing. Mol. Cell. Biol. 19, 6991–7000 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Prasad, J. & Manley, J. L. Regulation and substrate specificity of the SR protein kinase Clk/Sty. Mol. Cell. Biol. 23, 4139–4149 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ko, T. K., Kelly, E. & Pines, J. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J. Cell Sci. 114, 2591–2603 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Hirose, Y. & Manley, J. L. RNA polymerase II and the integration of nuclear events. Genes Dev. 14, 1415–1429 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Proudfoot, N. J., Furger, A. & Dye, M. J. Integrating mRNA processing with transcription. Cell 108, 501–512 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Maniatis, T. & Reed, R. An extensive network of coupling among gene expression machines. Nature 416, 499–506 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Dreyfuss, G., Matunis, M. J., Pinol-Roma, S. & Burd, C. G. hnRNP proteins and the biogenesis of mRNA. Annu. Rev. Biochem. 62, 289–321 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Mayeda, A. & Krainer, A. R. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 68, 365–375 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Singh, R., Valcarcel, J. & Green, M. R. Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Science 268, 1173–1176 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Ruskin, B., Zamore, P. D. & Green, M. R. A factor, U2AF, is required for U2 snRNP binding and splicing complex assembly. Cell 52, 207–219 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Labourier, E. et al. Antagonism between RSF1 and SR proteins for both splice-site recognition in vitro and Drosophila development. Genes Dev. 13, 740–753 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shin, C. & Manley, J. L. The SR protein SRp38 represses splicing in M phase cells. Cell 111, 407–417 (2002). Characterizes SRp38 as a general splicing repressor that is activated by dephosphorylation, and shows that the splicing machinery is repressed by SRp38 during M phase of the cell cycle.

    Article  CAS  PubMed  Google Scholar 

  34. Kanopka, A., Muhlemann, O. & Akusjarvi, G. Inhibition by SR proteins of splicing of a regulated adenovirus pre-mRNA. Nature 381, 535–538 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Valcarcel, J., Singh, R., Zamore, P. D. & Green, M. R. The protein Sex-lethal antagonizes the splicing factor U2AF to regulate alternative splicing of transformer pre-RNA. Nature 362, 171–175 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Amrein, H., Hedley, M. L. & Maniatis, T. The role of specific protein–RNA and protein–protein interactions in positive and negative control of pre-mRNA splicing by Transformer 2. Cell 76, 735–746 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Jensen, K. B. et al. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25, 359–371 (2000). Describes NOVA1 as a brain-specific splicing regulator by showing neuronal splicing defects in Nova1 -null mice.

    Article  CAS  PubMed  Google Scholar 

  38. Ponta, H., Sherman, L. & Herrlich, P. A. CD44: from adhesion molecules to signaling regulators. Nature Rev. Mol. Cell Biol. 4, 33–45 (2003).

    Article  CAS  Google Scholar 

  39. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Konig, H., Ponta, H. & Herrlich, P. Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator. EMBO J. 17, 2904–2913 (1998). Provides an initial characterization of CD44 v5 alternative-splicing regulation in response to activated Ras by identifying positively and negatively acting sequences.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Weg-Remers, S., Ponta, H., Herrlich, P. & Konig, H. Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J. 20, 4194–4203 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vernet, C. & Artzt, K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet. 13, 479–484 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Taylor, S. J. & Shalloway, D. An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis. Nature 368, 867–871 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Fumagalli, S., Totty, N. F., Hsuan, J. J. & Courtneidge, S. A. A target for Src in mitosis. Nature 368, 871–874 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Taylor, S. J., Resnick, R. J. & Shalloway, D. SAM68 exerts separable effects on cell cycle progression and apoptosis. BMC Cell Biol. 5, 5 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Matter, N., Herrlich, P. & Konig, H. Signal-dependent regulation of splicing via phosphorylation of SAM68. Nature 420, 691–695 (2002). Provides evidence that SAM68 activates CD44 v5 inclusion in response to phosphorylation by ERK.

    Article  CAS  PubMed  Google Scholar 

  47. Tacke, R. & Manley, J. L. The human splicing factors ASF/SF2 and SC35 possess distinct, functionally significant RNA binding specificities. EMBO J. 14, 3540–3551 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tacke, R. Tohyama, M., Ogawa, S., & Manley, J. L. Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing. Cell 93, 139–148 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Matter, N. et al. Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic signaling pathways. J. Biol. Chem. 275, 35353–35360 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Kashima, T. & Manley, J. L. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nature. Genet. 34, 460–463 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Lynch, K. W. & Weiss, A. A model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates protein kinase C and Ras. Mol. Cell. Biol. 20, 70–80 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lynch, K. W. & Weiss, A. A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer. J. Biol. Chem. 276, 24341–24347 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Rothrock, C., Cannon, B., Hahm, B. & Lynch. K. W. A conserved signal-responsive sequence mediates activation-induced alternative splicing of CD45. Mol. Cell 12, 1317–1324 (2003). Defines an ESS element as a signal-responsive cis -element that mediates CD45 v5 skipping.

    Article  CAS  PubMed  Google Scholar 

  55. Lemaire, R., Winne, A., Sarkissian, M. & Lafyatis, R. SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. Eur. J. Immunol. 29, 823–837 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. ten Dam, G. B. et al. Regulation of alternative splicing of CD45 by antagonistic effects of SR protein splicing factors. J. Immunol. 164, 5287–5295 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Wu, J. Y., Tang, H. & Havlioglu, N. Alternative pre-mRNA splicing and regulation of programmed cell death. Prog. Mol. Subcell. Biol. 31, 153–185 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Chalfant, C. E. et al. FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phasphatase 1. J. Biol. Chem. 276, 44848–44855 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405–414 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Utz, P. J., Hottelet, M., van Venrooij, W. J. & Anderson, P. Association of phosphorylated serine/Arg (SR) splicing factors with the U1-small ribonucleoprotein (snRNP) auroantigen complex accompanies apoptotic cell death. J. Exp. Med. 187, 547–560 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chalfant, C. E. et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J. Biol. Chem. 277, 12587–12595 (2002). Provides evidence that ceramide regulates alternative splicing of transcripts that encode apoptotic regulators.

    Article  CAS  PubMed  Google Scholar 

  62. Massiello, A. et al. Identification of two RNA cis-elements that function to regulate the 5′ splice site selection of Bcl-x pre-mRNA in response to ceramide. J. Biol. Chem. 279, 15799–15804 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Forch, P. et al. The apoptosis-promoting factor TIA1 is a regulator of alternative pre-mRNA splicing. Mol. Cell 6, 1089–1098 (2000). Describes the mechanism by which TIA1 regulates alternative splicing of Fas pre-mRNA.

    Article  CAS  PubMed  Google Scholar 

  64. Forch, P., Puig, O., Martinez, C., Seraphin, B. & Valcarcel, J. The splicing regulator TIA1 interacts with U1-C to promote U1 snRNP recruitment to 5′ splice sites. EMBO J. 21, 6882–6892 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Tian, Q., Streuli, M., Schlossman, S. F. & Anderson, P. A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell 67, 629–639 (1991).

    Article  CAS  PubMed  Google Scholar 

  66. Tian, Q., Taupin, J., Elledge, S., Robertson, M. & Anderson, P. Fas-mediated serine/threonine kinase (FAST) phosphorylates TIA1 during Fas-mediated apoptosis. J. Exp. Med. 182, 865–874 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Burns, C. G. et al. Removal of a single α-tubulin gene intron suppresses cell cycle arrest phenotypes of splicing factor mutations in Saccharomyces cerevisiae. Mol. Cell. Biol. 22, 801–815 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lopez, P. J. & Seraphin, B. Genomic-scale quantitative analysis of yeast pre-mRNA splicing: Implications for splice-site recognition. RNA 5, 1135–1137 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Segil, N., Guermah, M., Hoffmann, A., Roeder, R. G. & Heintz. N. Mitotic regulation of TFIID: inhibition of activator-dependent transcription and changes in subcellular localization. Genes Dev. 10, 2389–2400 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Akoulitchev, S. & Reinberg, D. The molecular mechanism of mitotic inhibition of TFIIH is mediated by phosphorylation of CDK7. Genes Dev. 12, 3541–3550 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Long, J. J., Leresche, A., Kriwacki, R. W. & Gottesfeld, J. M. Repression of TFIIH transcriptional activity and TFIIH associated cdk7 kinase activity at mitosis. Mol. Cell. Biol. 18, 1467–1476 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xu, Y. X., Hirose, Y., Zhou, X. Z., Lu, K. P. & Manley, J. L. Pin1 modulates the structure and function of human RNA polymerase II. Genes Dev. 17, 2765–2776 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Colgan, D. F., Murthy, K. G., Prives, C. & Manley, J. L. Cell-cycle related regulation of poly(A) polymerase by phosphorylation. Nature 384, 282–285 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Pyronnet, S., Dostie, J. & Sonenberg, N. Suppression of cap-dependent translation in mitosis. Genes Dev. 15, 2083–2093 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shin, C., Feng, Y. & Manley, J. L. Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427, 553–558 (2004). Provides evidence that SRp38 is responsible for heat-shock-induced splicing repression in vitro and in vivo.

    Article  CAS  PubMed  Google Scholar 

  76. Pyronnet, S. & Sonenberg, N. Cell-cycle-dependent translational control. Curr. Opin. Genet. Dev. 11, 13–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Trinkle-Mulcahy, L. et al. Nuclear organization of NIPP1, a regulatory subunit of protein phosphotase 1 that associates with pre-mRNA splicing factors. J. Cell Sci. 112, 157–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Beullens, M. & Bollen, M. The protein phosphatase-1 regulator NIPP1 is also a splicing factor involved in a late step of spliceosome assembly. J. Biol. Chem. 277, 19855–19860 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Boudrez, A. et al. NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry. J. Biol. Chem. 275, 25411–25417 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Boudrez, A., Beullens, M., Waelkens, E., Stalmans, W. & Bollen, M. Phosphorylation-dependent interaction between the splicing factors SAP155 and NIPP1. J. Biol. Chem. 277, 31834–31841 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Anderson, R. A., Boronenkov, I. V., Doughman, S. D., Kunz, J. & Loijens, J. C. Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J. Biol. Chem. 274, 9907–9910 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Toker, A. Phosphoinositides and signal transduction. Cell. Mol. Life Sci. 59, 761–779 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Boronenkov, I. V., Loijens, J. C., Umeda, M. & Anderson, R. A. Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol. Biol. Cell 9, 3547–3560 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Osborne, S. L., Thomas, C. L., Gschmeissner, S. & Schiavo, G. Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing. J. Cell Sci. 114, 2501–2511 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Yost, H. J., Petersen, R. B. & Lindquist, S. RNA metabolism: strategies for regulation in the heat shock response. Trends Genet. 6, 223–227 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. Gattoni, R. et al. The human hnRNP-M proteins: structure and relation with early heat shock-induced splicing arrest and chromosome mapping. Nucleic Acids Res. 24, 2535–2542 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Mahe, D. et al. Cloning of human 2H9 heterogeneous nuclear ribonucleoproteins. Relation with splicing and early heat shock-induced splicing arrest. J. Biol. Chem. 272, 1827–1836 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Jenkins, G. M. et al. Acute activation of de novo sphingolipid biosynthesis upon heat shock causes an accumulation of ceramide and subsequent dephosphorylation of SR proteins. J. Biol. Chem. 277, 42572–42578 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Carlsson, A. A paradigm shift in brain research. Science 294, 1021–1024 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Nieoullon, A. Dopamine and the regulation of cognition and attention. Prog. Neurobiol. 67, 53–83 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Berke, J. D., Paletzki, R. F., Aronson, G. J., Hyman, S. E. & Gerfen, C. R. A complex program of striatal gene expression induced by dopaminergic stimulation. J. Neurosci. 18, 5301–5310 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Berke, J. D. et al. Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. Neuron 32, 277–287 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Sgambato, V., Minassian, R., Nairn, A. C. & Hyman, S. E. Regulation of ania-6 splice variants by distinct signaling pathways in striatal neurons. J. Neurochem. 86, 153–164 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Boucher, L., Ouzounis, C. A., Enright, A. J. & Blencowe, B. J. A genome-wide survey of RS domain proteins. RNA 7, 1693–1701 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Dickinson, L. A., Edgar, A. J., Ehley, J. & Gottesfeld, J. M. Cyclin L is an RS domain protein involved in pre-mRNA splicing. J. Biol. Chem. 277, 25465–25473 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Hu, D., Mayeda, A., Trembley, J. H., Lahti, J. M. & Kidd, V. J. CDK11 complexes promote pre-mRNA splicing. J. Biol. Chem. 278, 8623–8629 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Trembley, J. H. et al. PITSLRE p110 protein kinases associate with transcription complexes and affect their activity. J. Biol. Chem. 277, 2589–2596 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Lahti, J. M., Xiang, J., Heath, L. S., Campana, D. & Kidd, V. J. PITSLRE protein kinase activity is associated with apoptosis. Mol. Cell. Biol. 15, 1–11 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tang, D., Gururajan, R. & Kidd, V. J. Phosphorylation of PITSLRE p110 isoforms accompanies their processing by caspases during Fas-mediated cell death. J. Biol. Chem. 273, 16601–16607 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  101. Yang, L. 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. 279, 11639–11648 (2004). Shows that cyclin L2 functions in splicing in vitro and that overexpression induces apoptosis.

    Article  CAS  PubMed  Google Scholar 

  102. Butler, A., Tsunoda, S., McCobb, D. P., Wei, A. & Salkoff, L. mSlo, a complex mouse gene encoding 'maxi' calcium-activated potassium channels. Science 261, 221–224 (1993).

    Article  CAS  PubMed  Google Scholar 

  103. Black, D. L. Splicing in the inner ear: a familiar tune, but what are the instruments? Neuron 20, 165–168 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Xie, J. & McCobb, D. P. Control of alternative splicing of potassium channels by stress hormones. Science 280, 443–446 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Xie, J. & Black, D. L. A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410, 936–939 (2001). Describes a sequence element in the STREX exon of the SLO transcript that is required for exon exclusion after depolarization-induced signalling through CaMKIV.

    Article  CAS  PubMed  Google Scholar 

  106. Yeakley, J. M. et al. Profiling alternative splicing on fiber-optic arrays. Nature Biotechnol. 20, 353–358 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to members of the Manley laboratory for their helpful comments, and to Inna Boluk for help with preparation of the manuscript. Work from the authors' laboratory was supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, 10027, New York, USA

    Chanseok Shin & James L. Manley

Authors
  1. Chanseok Shin
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  2. James L. Manley
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Corresponding author

Correspondence to James L. Manley.

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The authors declare no competing financial interests.

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DATABASES

Entrez

Ania-6

KCNMA1

SwissProt

ASF/SF2

BCL-X

CaMKIV

CDK11

CRK7

NIPP1

PTB

SAM68

SRp38

TIA1

U2AF

FURTHER INFORMATION

James L. Manley's laboratory

Glossary

EXONIC SPLICING ENHANCER

(ESE). A sequence that recruits serine-arginine rich (SR) proteins and related factors to pre-mRNA where they promote both constitutive and regulated splicing by interacting with each other, as well as with other factors including snRNP-associated RS-domain-containing proteins. Different ESEs are recognized by specific subsets of SR proteins.

SRPK

The first identified serine-arginine rich (SR)-protein kinase, which phosphorylates Ser residues in the RS domain of SR proteins. The kinase is predominantly localized in the cytoplasm of interphase cells, and shows increased kinase activity during mitosis. In mammals, the SRPK family consists of SRPK1 and SRPK2.

CLK/STY

A member of the CLK/STY-kinase family, which comprises dual-specificity kinases that can potentially phosphorylate Ser/Thr and Tyr residues. Targets include SR proteins, and the kinase itself is extensively autophosphorylated. The mammalian CLK/STY family consists of at least four kinases, CLK/STY, CLK2, CLK3 and CLK4.

EXONIC SPLICING SILENCER

(ESS). A sequence that recruits splicing-repressor proteins such as hnRNP A1. This protein inhibits the formation or stabilization of the snRNP–pre-mRNA complex. Repressor proteins can function directly by binding to SR proteins, or by blocking the binding of SR proteins to downstream ESEs. They can also inhibit the activity of the ESE complex, thereby preventing the use of adjacent 3′ splice sites.

KH-TYPE RNA-BINDING MOTIF

This K-homology (KH) motif, which was originally identified in the human hnRNP K protein, is important for RNA binding and probably binds RNA directly. Several proteins that contain KH-type RNA-binding motifs, including SAM68, are thought to function in signalling pathways, and are members of the signal transduction and activation of RNA (STAR) family.

CERAMIDE

The backbone molecule of sphingolipid, which is a component of membrane lipids. It is generated either by hydrolysis of more complex sphingolipids or by de novo synthesis, and recently has been shown to function as a regulator of the stress response and death-receptor-mediated apoptosis.

CYCLIN-DEPENDENT KINASE

(CDK). A protein kinase that is active only when it is in a complex with a regulatory cyclin protein. CDK–cyclin complexes phosphorylate specific target proteins to trigger different stages of the cell cycle, or different aspects of the RNA polymerase II transcription cycle.

NUCLEAR SPECKLE

An irregularly shaped nuclear organelle that can be visualized by immunofluorescence microscopy using anti-splicing-factor antibodies. Usually, approximately 25–50 speckles are present in the interphase mammalian nucleus, and they are thought to constitute storage/assembly sites for certain splicing factors.

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Shin, C., Manley, J. Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5, 727–738 (2004). https://doi.org/10.1038/nrm1467

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  • DOI: https://doi.org/10.1038/nrm1467

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