title: In CD28-costimulated human naïve CD4+ T cells, I-κB kinase controls the expression of cell cycle regulatory proteins via interleukin-2-independent mechanisms.
abstract: Stimulation of naïve CD4(+) T cells through engagement of the T-cell receptor (TCR) and the CD28 co-receptor initiates cell proliferation which critically depends on interleukin (IL)-2 secretion and subsequent autocrine signalling via the IL-2 receptor. However, several studies indicate that in CD28-costimulated T cells additional IL-2-independent signals are also required for cell proliferation. In this study, using a neutralizing anti-human IL-2 antibody and two selective, structurally unrelated, cell-permeable I-κB kinase (IKK) inhibitors, BMS-345541 and PS-1145, we show that in human naïve CD4(+) T cells stimulated through a short engagement of the TCR and the CD28 co-receptor, IKK controls the expression of the cell cycle regulatory proteins cyclin D3, cyclin E and cyclin-dependent kinase 2 (CDK2) and the stability of the F-box protein S-phase kinase-associated protein 2 (SKP2) and its co-factor CDC28 protein kinase regulatory subunit 1B (CKS1B), through IL-2-independent mechanisms.
authors.affiliation: Department of Medicine and Experimental Oncology, Section of Biochemistry, University of Turin, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lupino
authors.forename: Barbara
authors.initials: B
authors.lastname: Buccinnà
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramondetti
authors.forename: Annarosa
authors.initials: A
authors.lastname: Lomartire
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Marco
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricotti
authors.forename: Pier-Angelo
authors.initials: PA
authors.lastname: Tovo
authors.forename: Maria T
authors.initials: MT
authors.lastname: Rinaudo
authors.forename: Marco
authors.initials: M
authors.lastname: Piccinini
mesh_terms: D021581:Active Transport, Cell Nucleus; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D020672:I-kappa B Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D000911:Antibodies, Monoclonal; C534696:CCND3 protein, human; C475820:CCNE1 protein, human; D018106:CD28 Antigens; D017252:CD3 Complex; C436291:CDKN1B protein, human; C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D019927:Cyclin E; D006575:Heterocyclic Compounds, 3-Ring; D020672:I-kappa B Proteins; D007093:Imidazoles; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D015513:Oncogene Proteins; C456319:PS1145; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011810:Quinoxalines; D044786:S-Phase Kinase-Associated Proteins; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051550:I-kappa B Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases
references.citation: Science. 1995 Aug 4;269(5224):682-5
references.pmid: 7624798
references.citation: Science. 1993 Jul 30;261(5121):609-12
references.pmid: 7688139
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Blood. 2009 Feb 19;113(8):1689-98
references.pmid: 19001083
references.citation: Annu Rev Immunol. 2009;27:693-733
references.pmid: 19302050
references.citation: Nat Cell Biol. 1999 Aug;1(4):193-9
references.pmid: 10559916
references.citation: Nat Protoc. 2006;1(3):1458-61
references.pmid: 17406435
references.citation: Annu Rev Med. 2006;57:381-402
references.pmid: 16409156
references.citation: Nat Cell Biol. 2009 Apr;11(4):420-32
references.pmid: 19270694
references.citation: Anal Biochem. 1987 Nov 1;166(2):368-79
references.pmid: 2449095
references.citation: Cell Death Differ. 2006 May;13(5):826-33
references.pmid: 16439988
references.citation: J Immunol. 2001 Feb 1;166(3):1723-9
references.pmid: 11160217
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
references.pmid: 16911870
references.citation: Immunity. 1995 Nov;3(5):541-7
references.pmid: 7584144
references.citation: Immunity. 2006 Nov;25(5):701-15
references.pmid: 17098202
references.citation: J Biol Chem. 2003 Jan 17;278(3):1450-6
references.pmid: 12403772
references.citation: Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333-7
references.pmid: 2465550
references.citation: Cell. 2004 Jan 23;116(2):221-34
references.pmid: 14744433
references.citation: J Biol Chem. 1993 Feb 25;268(6):4113-9
references.pmid: 8382693
references.citation: Biochem J. 2007 Dec 15;408(3):297-315
references.pmid: 17850214
references.citation: J Exp Med. 1997 Jun 2;185(11):1897-907
references.pmid: 9166419
references.citation: J Biol Chem. 2002 May 10;277(19):16733-43
references.pmid: 11875070
references.citation: Nature. 1991 Aug 15;352(6336):621-4
references.pmid: 1830926
references.citation: Nat Cell Biol. 1999 Aug;1(4):207-14
references.pmid: 10559918
references.citation: Immunity. 1998 Jan;8(1):89-95
references.pmid: 9462514
references.citation: Nat Cell Biol. 2001 Mar;3(3):321-4
references.pmid: 11231585
references.citation: J Immunol. 1999 Jun 1;162(11):6442-50
references.pmid: 10352258
references.citation: Bioorg Med Chem Lett. 2003 Jul 21;13(14):2419-22
references.pmid: 12824047
references.citation: Curr Biol. 2001 Jun 5;11(11):R431-5
references.pmid: 11516665
references.citation: J Biol Chem. 2007 May 25;282(21):15462-70
references.pmid: 17409098
references.citation: Nat Rev Drug Discov. 2004 Jan;3(1):17-26
references.pmid: 14708018
references.citation: Cell Cycle. 2006 Sep;5(18):2123-9
references.pmid: 16969077
references.citation: Cell Cycle. 2004 Jul;3(7):850-2
references.pmid: 15190201
references.citation: Cell Death Differ. 2006 May;13(5):834-42
references.pmid: 16410801
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11796-801
references.pmid: 12195013
references.citation: Methods Enzymol. 1990;182:425-41
references.pmid: 2314252
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4566-71
references.pmid: 15070758
references.citation: Nat Immunol. 2005 May;6(5):472-80
references.pmid: 15834410
references.citation: J Immunol. 2000 Jan 1;164(1):144-51
references.pmid: 10605005
references.citation: Mol Cell Biol. 1997 Jul;17(7):4051-8
references.pmid: 9199340
references.citation: Int Immunol. 2004 Dec;16(12):1711-21
references.pmid: 15492022
references.citation: J Immunol. 2006 Mar 1;176(5):2730-8
references.pmid: 16493028
references.citation: Nat Cell Biol. 2009 Apr;11(4):397-408
references.pmid: 19270695
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360
references.citation: Mol Cell. 2001 Mar;7(3):639-50
references.pmid: 11463388
references.citation: J Biol Chem. 2004 Jul 9;279(28):28827-30
references.pmid: 15084594
references.citation: J Biol Chem. 2001 Jun 15;276(24):21976-83
references.pmid: 11297537
references.citation: Trends Biochem Sci. 2005 Nov;30(11):630-41
references.pmid: 16236519