Signals and their transduction pathways regulating alternative splicing: A new dimension of the human genome

Human Molecular Genetics

Volumn 11, Issue 20, 2002, Pages 2409-2416

  Stamm, Stefan ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

MITOGEN ACTIVATED PROTEIN KINASE KINASE; PHOSPHATIDYLINOSITOL KINASE; PROTEIN KINASE C; RAS PROTEIN; REGULATOR PROTEIN; SYNAPTOPHYSIN;

ALTERNATIVE RNA SPLICING; CELL FUNCTION; CELLULAR DISTRIBUTION; CONCENTRATION (PARAMETERS); CONTROLLED STUDY; HUMAN; HUMAN GENOME; MEDICAL GENETICS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS; REVIEW; SIGNAL TRANSDUCTION;

EID: 0036798006     PISSN: 09646906     EISSN: None     Source Type: Journal    
DOI: 10.1093/hmg/11.20.2409     Document Type: Review

References (101)

1. Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W et al. (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860-921.
2. Modrek, B., Resch, A., Grasso, C. and Lee, C. (2001) Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res., 29, 2850-2859.
3. Venter, J.C., Adams, M.D., Myers, E.W., Li, P.W., Mural, R.J., Sutton, G.G., Smith, H.O., Yandell, M., Evans, C.A., Holt, R.A. et al. (2001) The sequence of the human genome. Science, 291, 1304-1351.
4. Harrison, P.M., Kumar, A., Lang, N., Snyder, M. and Gerstein, M. (2002) A question of size: the eukaryotic proteome and the problems in defining it. Nucleic Acids Res., 30, 1083-1090.
5. Neubauer, G., King, A., Rappsilber, J., Calvio, C., Watson, M., Ajuh, P., Sleeman, J., Lamond, A. and Mann, M. (1998) Mass spectometry and EST-database searching allows characterization of the multiprotein spliceosome complex. Nat. Genet., 20, 46-50.
6. Will, C.L. and Luhrmann, R. (2001) Spliceosomal UsnRNP biogenesis, structure and function. Curr. Opin. Cell Biol., 13, 290-301.
7. Hastings, M.L. and Krainer, A.R. (2001) Pre-mRNA splicing in the new millennium. Curr. Opin. Cell Biol., 13, 302-309.
8. Caceres, J.E and Kornblihtt, A.R. (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet., 18, 186-193.
9. Smith, C.W. and Valcarcel, J. (2000) Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem. Sci., 25, 381-388.
10. Blencowe, B.J. (2000) Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem. Sci., 25, 106-110.
11. Dreyfuss, G., Kim, V.N. and Kataoka, N. (2002) Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell Biol., 3, 195-205.
12. Graveley, BR. (2000) Sorting out the complexity of SR protein function. RNA, 6, 1197-1211.
13. Hanamura, A., Caceres, J.F., Mayeda, A., Franza, B.R. and Krainer, A.R. (1998) Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors. RNA, 4, 430-444.
14. Jensen, K.B., Dredge, B.K., Stefani, G., Zhong, R., Buckanovich, R.J., Okano, H.J., Yang, Y.Y. and Darnell, R.B. (2000) Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron, 25, 359-371.
15. Markovtsov, V, Nikolic, J.M., Goldman, J.A., Turck, C.W., Chou, M.Y. and Black, D.L. (2000) Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol. Cell Biol., 20, 7463-7479.
16. Komatsu, M., Kominami, E., Arahata, K. and Tsukahara, T. (1999) Cloning and characterization of two neural-salient serine/arginine-rich (NSSR) proteins involved in the regulation of alternative splicing in neurons. Genes to Cells, 4, 593-606.
17. Sanford, JR. and Bruzik, J.P. (1999) Developmental regulation of SR protein phosphorylation and activity. Genes Dev, 13, 1513-1518.
18. Mahe, D., Fischer, N., Decimo, D. and Fuchs, J.P. (2000) Spatiotemporal regulation of hnRNP M and 2119 gene expression during mouse embryonic development. Biochim. Biophys. Acta, 1492, 414-424.
19. Stamm, S., Zhu, J., Nakai, K., Stoilov, R, Stoss, O. and Zhang, M.Q. (2000) An alternative-exon database and its statistical analysis. DNA Cell Biol., 19, 739-756.
20. Rave-Harel, N., Kerem, E., Nissim-Rafinia, M., Madjar, I., Goshen, R., Augarten, A., Rahat, A., Hurwitz, A., Darvasi, A. and Kerem, B. (1997) The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. Am. J. Hum. Genet., 60, 87-94.
21. Slaugenhaupt, S.A., Blumenfeld, A., Gill, S.P., Leyne, M., Mull, J., Cuajungco, M.P., Liebert, C.B., Chadwick, B., Idelson, M., Reznik, L. et al. (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J Hum. Genet., 68, 598-605.
22. Nissim-Rafinia, M. and Kerem, B. (2002) Splicing regulation as a potential genetic modifier. Trends Genet., 18, 123-127.
23. Cramer, P, Srebrow, A., Kadener, S., Werbajh, S., de la Mata, M., Melen, G., Nogues, G. and Kornblihtt, A.R. (2001) Coordination between transcription and pre-mRNA processing. FEBS Lett., 498, 179-182.
24. Minvielle-Sebastia, L. and Keller, W (1999) mRNA polyadenylation and its coupling to other RNA processing reactions and to transcription. Curr. Opin. Cell Biol., 11, 352-357.
25. Rueter, S.M., Dawson, T.R. and Emeson, R.B. (1999) Regulation of alternative splicing by RNA editing. Nature, 399, 75-80.
26. Reed R. and Hurt, E. (2002) A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell, 108, 523-531.
27. Maniatis, T. and Reed, R. (2002) An extensive network of coupling among gene expression machines. Nature, 416, 499-506.
28. Bentley, D. (2002) The mRNA assembly line: transcription and processing machines in the same factory. Curr. Opin. Cell Biol., 14, 336-342.
29. Cramer, R, Pesce, C.G., Baralle, F.E. and Kornblihtt, A.R. (1997) Functional association between promoter structure and transcript alternative splicing. Proc. Natl Acad. Sci. USA, 94, 11456-11460.
30. Philips, A.V. and Cooper, T.A. (2000) RNA processing and human disease. Cell. Mol. Life Sci., 57, 235-249.
31. Stoss, O., Stoilov, P., Daoud, R., Hartmann, A.M., Olbrich, M. and Stamm, S. (2000) Misregulation of pre-mRNA splicing that causes human diseases. Gene Ther. Mol. Biol., 5, 9-28.
32. Stoilov, P, Meshorer, E., Gencheva, M., Glick, D., Soreq, H. and Stamm, S. (2002) Defects in pre-mRNA processing as causes of and predisposition to diseases. DNA Cell Biol., in press.
33. Nakai, K. and Sakamoto, H. (1994) Construction of a novel database containing aberrant splicing mutations of mammalian genes. Gene, 141, 171-177.
34. Krawczak, M., Reiss, J. and Cooper, D.N. (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet., 90, 41-54.
35. Cartegni, L., Chew, S.L. and Kramer, A.R. (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet., 3, 285-298.
36. Stickeler, E., Kittrell, F., Medina, D. and Berget, S.M. (1999) Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene, 18, 3574-3582.
37. Scorilas, A., Kyriakopoulou, L., Katsaros, D. and Diamandis, E.P. (2001) Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer. Br. J Cancer, 85, 190-198.
38. Daoud, R., Mies, G., Smialowska, A., Oláh, L., Hossmann, K. and Stamm, S. (2002) Ischemia induces a translocation of the splicing factor tra2-β1 and changes alternative splicing patterns in the brain. J Neurosci., 22, 5889-5899.
39. Pearn, J. (1980) Classification of spinal muscular atrophies. Lancet, 1, 919-922.
40. Wirth, B. (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum. Mutat., 15, 228-237.
41. Lorson, C.L., Hahnen, E., Androphy, E.J. and Wirth, B. (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA, 96, 6307-6311.
42. DiDonato, C.J., Lorson, C.L., De Repentigny, Y., Simard, L., Chartrand, C., Androphy, E.J. and Kothary, R. (2001) Regulation of murine survival motor neuron (Smn) protein levels by modifying Smn exon 7 splicing. Hum. Mol. Genet., 10, 2727-2736.
43. Young, P.J., DiDonato, C.J., Hu, D., Kothary, R., Androphy, E.J. and Lorson, C.L. (2002) SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2β1. Hum. Mol. Genet., 11, 577-587.
44. Hofmann, Y., Lorson, C.L., Stamm, S., Androphy, E.J. and Wirth, B. (2000) Htra2-β1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc. Natl Acad. Sci. USA, 97, 9618-9623.
45. Chang, J.G., Hsieh-Li, H.M., Jong, Y.J., Wang, N.M., Tsai, C.H. and Li, H. (2001) Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl Acad. Sci. USA, 98, 9808-9813.
46. Andreassi, C., Jarecki, J., Zhou, J., Coovert, D.D., Monani, U.R., Chen, X., Whitney, M., Pollok, B., Zhang, M., Androphy, E. et al. (2001) Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum. Mol. Genet., 10, 2841-2849.
47. Grabowski, P.L. and Black, D.L. (2001) Alternative RNA splicing in the nervous system. Prog. Neurobiol., 65, 289-308.
48. Stamm, S. and Thanaraj, T.A. (2002) Prediction and statistical analysis of alternatively spliced exons. Prog. Mol. Sub. Biol., in press.
49. Kaufer, D., Friedman, A., Seidman, S. and Soreq, H. (1998) Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature, 393, 373-377.
50. Stork, O., Stork, S., Pape, H.C. and Obata, K. (2001) Identification of genes expressed in the amygdala during the formation of fear memory. Learn. Mem., 8, 209-219.
51. Amir-Ahmady, B. and Salati, L.M. (2001) Regulation of the processing of glucose-6-phosphate dehydrogenase mRNA by nutritional status. J. Biol. Chem., 276, 10514-10523.
52. Tao, H., Szeszel-Fedorowicz, W., Amir-Ahmady, B., Gibson, M.A., Stabile, L.P. and Salati, L.M. (2002) Inhibition of the splicing of glucose-6-phosphate dehydrogenase pre-mRNA by polyunsaturated fatty acids. J. Biol. Chem., 277, 31270-31278.
53. Berke, J.D., Sgambato, V., Zhu, P.P., Lavoie, B., Vincent, M., Krause, M. and Hyman, S.E. (2001) Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin. Neuron, 32, 277-287.
54. A receptor subunit and splice variant expression in rats treated with chronic intermittent ethanol. Alcohol Clin. Exp. Res., 25, 819-828.
55. Lynch, K.W. and Weiss, A. (2000) 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.
56. König, H., Ponta, H. and Herrlich, P. (1998) Coupling of signal transduction to alternative pre-mRNA splicing by a composite splice regulator. EMBO J, 17, 2904-2913.
57. 2+. Curr Biol., 6, 1642-1652.
58. Hartmann, A.M., Rujescu, D., Giannakouros, T., Nikolakaki, E., Goedert, M., Mandelkow, E.M., Gao, Q.S., Andreadis, A. and Stamm, S. (2001) Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol. Cell. Neurosci., 18, 80-90.
59. Pilch, B., Allemand, E., Facompre, M., Bailly, C., Rion, J.F., Soret, J. and Tazi, J. (2001) Specific inhibition of serine- and arginine-rich splicing factors phosphorylation, spliceosome assembly, and splicing by the antitumor drug NB-506. Cancer Res., 61, 6876-6884.
60. Caceres, J.F., Screaton, G.R. and Krainer, A.R. (1998) A specific subset of SR proteins shuttles continously between the nucleus and the cytoplasm. Genes Dev., 12, 55-66.
61. van der Houven van Oordt, W., Diaz-Meco, M.T., Lozano, J., Kramer, A.R., Moscat, J. and Caceres, J.F., (2000) The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J. Cell Biol., 149, 307-316.
62. Denegri, M., Chiodi, I., Corioni, M., Cobianchi, F., Riva, S. and Biamonti, G. (2001) Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors. Mol. Biol. Cell., 12, 3502-3514.
63. Chalfant, C.E., Watson, J.E., Bisnauth, L.D., Kang, J.B., Patel, N., Obeid, L.M., Eichler, D.C. and Cooper, D.R. (1998) Insulin regulates protein kinase Coll expression through enhanced exon inclusion in L6 skeletal muscle cells. A novel mechanism of insulin- and insulin-like growth factor-I-induced 5′ splice site selection. J Biol. Chem., 273, 910-916.
64. Du, K., Peng, Y., Greenbaum, L.E., Haber, B.A. and Taub, R. (1997) HRS/SRp40-mediated inclusion of the fibronectin EIIIB exon, a possible cause of increased EIIIB expression in proliferating liver. Mol. Cell Biol., 17, 4096-4104.
65. Patel, N.A., Chalfant, C.E,, Watson, J.E., Wyatt, J.R., Dean, N.M., Eichler, D.C. and Cooper, D.R. (2001) Insulin regulates alternative splicing of protein kinase CβII through a phosphatidylinositol 3-kinase-dependent pathway involving the nuclear serine/arginine-rich splicing factor, SRp40, in skeletal muscle cells. J Biol. Chem., 276, 22648-22654.
66. Weg-Remers, S., Ponta, H., Herrlich, P. and Konig, H. (2001) Regulation of alternative pre-mRNA splicing by the ERK MAP-kinase pathway. EMBO J, 20, 4194-4203.
67. Matter, N., Marx, M., Weg-Remers, S., Ponta, H., Herrlich, P. and Konig, H, (2000) Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic signaling pathways. J Biol. Chem., 275, 35353-35360.
68. Daoud, R., Da Penha Berzaghi, M., Siedler, F., Hubener, M. and Stamm, S. (1999) Activity-dependent regulation of alternative splicing patterns in the rat brain. Eur. J. Neurosci., 11, 788-802.
69. Xie, J. and Black, D.L. (2001) A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature, 410, 936-939.
70. Jiang, H.-H., Zhang, W.-J., Rao, Y. and Wu, J.Y. (1998) Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors. Proc. Natl Acad. Sci. USA, 95, 9155-9160.
71. Cote, J., Dupuis, S. and Wu, J.Y. (2001) Polypyrimidine track-binding protein binding downstream of caspase-2 alternative exon 9 represses its inclusion. J Biol. Chem., 276, 8535-8543.
72. Modrek, B. and Lee, C. (2002) A genomic view of alternative splicing. Nat. Genet., 30, 13-19.
73. Clark, T.A., Sugnet, C.W. and Ares, M., Jr (2002) Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays. Science, 296, 907-910.
74. Yeakley, J.M., Fan, J.B., Doucet, D., Luo, L., Wickham, E., Ye, Z., Chee, M.S. and Fu, X.D. (2002) Profiling alternative splicing on fiberoptic arrays. Nat. Biotechnol., 20, 353-358.
75. Lemaire, R., Winne, A., Sarkissian, M. and Lafayatis, R. (1999) SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. Eur. J. Immunol., 29, 823-837.
76. Shifrin, V.I. and Neel, B.G. (1993) Growth factor-inducible alternative splicing of nontransmembrane phosphotyrosine phosphatase PTP-1B pre-mRNA. J. Biol. Chem., 268, 25376-25384.
77. Ishizuka, T., Kajita, K., Yamada, K., Miura, A., Kanoh, Y., Ishizawa, M., Wada, H., Itaya, S., Yamamoto, M., Yasuda, K. et al. (1996) Insulin regulated PKC isoform mRNA in rat adipocytes. Diabetes Res. Clin. Pract., 33, 159-167.
78. Sell, S.M., Reese, D. and Ossowski, V.M. (1994) Insulin-inducible changes in insulin receptor mRNA splice variants. J. Biol. Chem., 269, 30769-30772.
79. Scotet, E. and Houssaint, E. (1998) Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2. Oncogene, 17, 67-76.
80. Mackay, C.R., Terpe, H.J., Stauder, R., Marston, W.L., Stark, H. and Gunthert, U. (1994) Expression and modulation of CD44 variant isoforms in humans. J. Cell Biol., 124, 71-82.
81. Eissa, N.T., Strauss, A.J., Haggerty, C.M., Choo, E.K., Chu, S.C. and Moss, J. (1996) Alternative splicing of human inducible nitric-oxide synthase messenger-RNA - tissue-specific regulation and induction by cytokines J. Biol. Chem., 271, 27184-27187.
82. McKay, N.G., Hunter, D.J., Haites, N.E. and Power, D.A. (1994) Regulation of alternative splicing of the fibronectin IIICS domain by cytokines. Biochem. Biophys. Res. Commun., 199, 1005-1011.
83. Wang, A.D., Cohen, S., Palmer, E. and Sheppard, D. (1991) Polarized regulation of fibronectin secretion and alternative splicing by transforming growth factor β. J. Biol. Chem., 266, 15598-15601.
84. Balza, E., Borsi, L., Allemanni, G. and Zardi, L. (1988) Transforming growth factor β regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts. FEBS Lett., 228, 42-44.
85. Kosaki, A. and Webster, N.J. (1993) Effect of dexamethasone on the alternative splicing of the insulin receptor mRNA and insulin action in HepG2 hepatoma cells. J Biol. Chem., 268, 21990-21996.
86. Xie, J. and McCobb, D.P. (1998) Control of alternative splicing of potassium channels by stress hormones. Science, 280, 443-446.
87. Metheny, L.J. and Skuse, G.R. (1996) NF1 mRNA isoform expression in PC12 cells: modulation by extrinsic factors. Exp. Cell Res., 228, 44-49.
88. Smith, M.A., Fanger, G.R., O'Connor, L.T., Bridle, P. and Maue, R.A. (1997) Selective regulation of agrin mRNA induction and alternative splicing in PC12 cells by Ras-dependent actions of nerve growth factor. J. Biol. Chem., 272, 15675-15681.
89. Helme-Guizon, A., Davis, S., Israel, M., Lesbats, B., Mallet, J., Laroche, S. and Hicks, A. (1998) Increase in syntaxin 1B and glutamate release in mossy fibre terminals following induction of LTP in the dentate gyrus: a candidate molecular mechanism underlying transsynaptic plasticity. Eur. J. Neurosci., 10, 2231-2237.
90. Rodger, J., Davis, S., Laroche, S., Mallet, J. and Hicks, A. (1998) Induction of long-term potentiation in vivo regulates alternative splicing to alter syntaxin 3 isoform expression in rat dentate gyrus. J. Neurochem., 71, 666-675.
91. Kamphuis, W., Monyer, H., De Rijk, T.C. and Lopes da Silva, F.H. (1992) Hippocampal kindling increases the expression of glutamate receptor-A Flip and -B Flip mRNA in dentate granule cells. Neurosci. Lett., 148, 51-54.
92. Bottai, D., Guzowski, J.F., Schwarz, M.K., Kang, S.H., Xiao, B., Lanahan, A., Worley, P.F. and Seeburg, R.H. (2002) Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression. J. Neurosci., 22, 167-175.
93. Hayakawa, M., Endo, H., Hamamoto, T. and Kagawa, Y. (1998) Acidic stimulation induces a negative regulatory factor that affects alternative exon selection in vitro in human ATP synthase γ-subunit pre-mRNA. Biochem. Biophys. Res. Commun., 251, 603-608.
94. Borsi, L., Balza, E., Gaggero, B., Allemanni, G. and Zardi, L. (1995) The alternative splicing pattern of the tenascin-C pre-mRNA is controlled by the extracellular pH. J. Biol. Chem., 270, 6243-6245.
95. Meshorer, E., Erb, C., Gazit, R., Pavlovsky, L., Kaufer, D., Friedman, A., Glick, D., Ben-Arie, N. and Soreq, H. (2002) Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity. Science, 295, 508-512.
96. Ars, E., Serra, E., de la Luna, S., Estivill, X. and Lazaro, C. (2000) Cold shock induces the insertion of a cryptic exon in the neurofibromatosis type 1 (NF1) mRNA. Nucleic Acids Res., 28, 1307-1312.
97. Shen, J., Beall, C.J. and Hirsh, J. (1993) Tissue-specific alternative splicing of the Drosophila dopa decarboxylase gene is affected by heat shock. Mol. Cell Biol., 13, 4549-4555.
98. Kimura, K., Asami, K. and Yamamoto, M. (1997) Effect of heat shock treatment on the production of variant testosterone-repressed prostate message-2 (TRPM-2) mRNA in culture cells. Cell. Biochem. Funct., 15, 251-257.
99. Takechi, H., Hosokawa, N., Hirayoshi, K. and Nagata, K. (1994) Alternative 5′ splice site selection induced by heat shock. Mol. Cell Biol., 14, 567-575.
100. Marrs, K.A. and Walbot, V. (1997) Expression and RNA splicing of the maize glutathione S-transterase Bronze2 gene is regulated by cadmium and other stresses. Plant Physiol., 113, 93-102.
101. Tabaczewski, P., Shirwan, H., Lewis, K. and Stroynowski, I. (1994) Alternative splicing of class Ib major histocompatibility complex transcripts in vivo leads to the expression of soluble Qa-2 molecules in murine blood. Proc. Natl Acad. Sci. USA, 91, 1883-1887.