title: Accumulation of splice variants and transcripts in response to PI3K inhibition in T cells.
abstract: BACKGROUND
  Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA.
  
  
  OBJECTIVE
  Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing.
  
  
  METHODS
  To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression.
  
  
  RESULTS
  Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry.
  
  
  CONCLUSIONS
  PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
authors: Institute for Virology and Immunobiology, University of Wuerzburg, Versbacher, Wuerzburg, Germany.
authors: Alice
authors: A
authors: Riedel
authors: Boitumelo
authors: B
authors: Mofolo
authors: Elita
authors: E
authors: Avota
authors: Sibylle
authors: S
authors: Schneider-Schaulies
authors: Ayton
authors: A
authors: Meintjes
authors: Nicola
authors: N
authors: Mulder
authors: Susanne
authors: S
authors: Kneitz
mesh_terms: D000465:Algorithms; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008459:Measles virus / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013491:Suppressor Factors, Immunologic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology*
chemical_list: D017931:DNA Primers; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D013491:Suppressor Factors, Immunologic
references: Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12122-6
references: 1465449
references: Nat Med. 2001 Jun;7(6):725-31
references: 11385511
references: J Virol. 2003 Feb;77(3):2105-15
references: 12525645
references: Circulation. 2007 Oct 9;116(15):1707-13
references: 17875970
references: Med Microbiol Immunol. 2010 Aug;199(3):227-37
references: 20376484
references: J Biol Chem. 2001 Dec 28;276(52):48908-14
references: 11684676
references: Immunol Res. 2010 Jul;47(1-3):216-27
references: 20066508
references: Curr Top Microbiol Immunol. 2009;339:147-75
references: 20012528
references: Curr Biol. 1996 Apr 1;6(4):438-45
references: 8723348
references: PLoS One. 2009 Nov 19;4(11):e7906
references: 19936255
references: J Virol. 2004 Sep;78(17):9552-9
references: 15308747
references: Immunol Lett. 2011 Jul;138(1):15-8
references: 21333676
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7797-802
references: 18509048
references: Nat Rev Immunol. 2004 Dec;4(12):931-40
references: 15573128
references: Cell Microbiol. 2006 Nov;8(11):1826-39
references: 16824039
references: Cell Death Dis. 2011 Jan 13;2:e114
references: 21368886
references: Nat Rev Immunol. 2009 Jul;9(7):503-13
references: 19498380
references: Biochem J. 2009 Jan 1;417(1):15-27
references: 19061484
references: Curr Opin Immunol. 2011 Feb;23(1):96-103
references: 21146386
references: Immunol Rev. 2010 Jul;236:176-89
references: 20636817
references: Adv Exp Med Biol. 2009;665:3-16
references: 20429412
references: Genomics. 2000 Oct 1;69(1):104-12
references: 11013080
references: Cell Adh Migr. 2011 Mar-Apr;5(2):150-9
references: 21350330
references: Bioinformatics. 2005 May 1;21(9):2067-75
references: 15657102
references: Mol Endocrinol. 2007 Oct;21(10):2334-49
references: 17609436
references: J Biol Chem. 2011 Mar 4;286(9):7661-8
references: 21216954
references: Mol Cell. 2009 Feb 27;33(4):462-71
references: 19250907
references: J Virol. 1997 Oct;71(10):7214-9
references: 9311794
references: J Immunol. 2006 Jan 15;176(2):949-56
references: 16393980
references: Dev Cell. 2010 Apr 20;18(4):592-604
references: 20412774
references: BMC Bioinformatics. 2007 Nov 15;8:449
references: 18005448
references: J Mol Biol. 1990 Jan 5;211(1):11-6
references: 2299665
references: Curr Top Microbiol Immunol. 2010;346:31-56
references: 20517722
references: BMC Genomics. 2010 Sep 14;11:496
references: 20840771
references: BMC Genomics. 2009 Nov 12;10:519
references: 19909511
references: J Biol Chem. 2010 Mar 12;285(11):7964-76
references: 20068046
references: PLoS Pathog. 2009 Oct;5(10):e1000623
references: 19834551
references: J Biol Chem. 2001 May 18;276(20):17083-91
references: 11278750
references: Curr Top Microbiol Immunol. 2010;346:57-85
references: 20563708
references: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13194-9
references: 8917567
references: Nucleic Acids Res. 2009 Sep;37(16):e107
references: 19528075
references: Nature. 2008 Nov 27;456(7221):470-6
references: 18978772
references: Genes Dev. 2000 Mar 1;14(5):505-20
references: 10716940
references: Int J Biochem Cell Biol. 2007;39(11):2031-48
references: 17507279
references: Oncogene. 2005 Nov 14;24(50):7410-25
references: 16288288
references: Cell Cycle. 2009 Aug;8(15):2343-6
references: 19571673
references: RNA. 2012 May;18(5):1029-40
references: 22454538
references: Rev Med Virol. 2006 Jan-Feb;16(1):49-63
references: 16237742
references: Eur J Immunol. 2011 Jan;41(1):151-63
references: 21182086
references: Curr Opin Immunol. 2010 Jun;22(3):348-54
references: 20381328
references: Science. 2009 Jan 30;323(5914):644-8
references: 19179534
references: Immunol Rev. 2009 Mar;228(1):253-72
references: 19290933
references: Int Immunol. 2006 Jul;18(7):1189-96
references: 16740602
references: J Immunol. 2011 Dec 15;187(12):6256-67
references: 22075696
references: FEBS J. 2011 Sep;278(18):3246-55
references: 21794093
references: Springer Semin Immunopathol. 2006 Oct;28(2):185-93
references: 16953440
references: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2444-9
references: 12604780
references: Immunity. 1998 Nov;9(5):657-68
references: 9846487
references: Nature. 1998 Jun 4;393(6684):483-7
references: 9624006
references: BMC Genomics. 2008 May 16;9:225
references: 18485203
references: Nat Rev Microbiol. 2005 Oct;3(10):799-808
references: 16175175
references: J Gen Virol. 2006 Jun;87(Pt 6):1423-1438
references: 16690907
references: Nat Immunol. 2002 May;3(5):477-82
references: 11953749
references: Bioinformatics. 2003 Jan 22;19(2):185-93
references: 12538238
references: Genome Biol. 2007;8(4):R64
references: 17456239
references: Prog Nucleic Acid Res Mol Biol. 2004;78:37-88
references: 15210328