title: E2F2 and CREB cooperatively regulate transcriptional activity of cell cycle genes.
abstract: E2F2 is essential for the maintenance of T lymphocyte quiescence. To identify the full set of E2F2 target genes, and to gain further understanding of the role of E2F2 in transcriptional regulation, we have performed ChIP-chip analyses across the genome of lymph node-derived T lymphocytes. Here we show that during quiescence, E2F2 binds the promoters of a large number of genes involved in DNA metabolism and cell cycle regulation, concomitant with their transcriptional silencing. A comparison of ChIP-chip data with expression profiling data on resting E2f2(-)(/)(-) T lymphocytes identified a subset of 51 E2F2-specific target genes, most of which are upregulated on E2F2 loss. Luciferase reporter assays showed a retinoblastoma-independent role for E2F2 in the negative regulation of these target genes. Importantly, we show that the DNA binding activity of the transcription factor CREB contributes to E2F2-mediated repression of Mcm5 and Chk1 promoters. siRNA-mediated CREB knockdown, expression of a dominant negative KCREB mutant or disruption of CREB binding by mutating a CRE motif on Mcm5 promoter, relieved E2F2-mediated transcriptional repression. Taken together, our data uncover a new regulatory mechanism for E2F-mediated transcriptional control, whereby E2F2 and CREB cooperate in the transcriptional repression of a subset of E2F2 target genes.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, Bilbao 48940, Spain and Department of Biochemistry and Molecular Biology, University of the Basque Country, UPV/EHU, Bilbao 48940, Spain.
authors.forename: Usua
authors.initials: U
authors.lastname: Laresgoiti
authors.forename: Aintzane
authors.initials: A
authors.lastname: Apraiz
authors.forename: Miguel
authors.initials: M
authors.lastname: Olea
authors.forename: Jone
authors.initials: J
authors.lastname: Mitxelena
authors.forename: Nerea
authors.initials: N
authors.lastname: Osinalde
authors.forename: José A
authors.initials: JA
authors.lastname: Rodriguez
authors.forename: Asier
authors.initials: A
authors.lastname: Fullaondo
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018816:Genes, cdc; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D012097:Repressor Proteins
references.citation: Curr Mol Med. 2006 Nov;6(7):739-48
references.pmid: 17100600
references.citation: Genome Res. 2003 May;13(5):773-80
references.pmid: 12727897
references.citation: Mol Cell Biol. 2001 Dec;21(24):8547-64
references.pmid: 11713289
references.citation: Genes Dev. 2004 Jun 15;18(12):1413-22
references.pmid: 15175242
references.citation: Mol Cell Biol. 1997 Dec;17(12):6994-7007
references.pmid: 9372931
references.citation: Nucleic Acids Res. 2011 May;39(9):3558-73
references.pmid: 21247883
references.citation: Genes Dev. 1997 Jul 15;11(14):1853-63
references.pmid: 9242492
references.citation: Immunity. 2001 Dec;15(6):959-70
references.pmid: 11754817
references.citation: Nature. 1996 Jan 4;379(6560):81-5
references.pmid: 8538746
references.citation: PLoS One. 2010 Aug 27;5(8):e12452
references.pmid: 20805990
references.citation: Mol Cell Biol. 2007 Dec;27(24):8713-28
references.pmid: 17923680
references.citation: Cell Death Differ. 2005 Apr;12(4):369-76
references.pmid: 15731768
references.citation: EMBO J. 2004 Dec 8;23(24):4709-16
references.pmid: 15538380
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W551-4
references.pmid: 16845068
references.citation: EMBO J. 2002 Nov 1;21(21):5775-86
references.pmid: 12411495
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2858-63
references.pmid: 10077601
references.citation: J Virol. 2004 Oct;78(19):10336-47
references.pmid: 15367600
references.citation: Proc Natl Acad Sci U S A. 1990 Jun;87(11):4320-4
references.pmid: 2140898
references.citation: J Biol Chem. 2002 Nov 1;277(44):42268-79
references.pmid: 12200429
references.citation: J Biol Chem. 2008 Dec 5;283(49):34305-14
references.pmid: 18840615
references.citation: Cell. 1994 Jul 15;78(1):161-72
references.pmid: 8033208
references.citation: Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609
references.pmid: 11483993
references.citation: Genes Dev. 2009 Jan 1;23(1):37-53
references.pmid: 19136625
references.citation: Nucleic Acids Res. 2012 Apr;40(8):3511-23
references.pmid: 22180533
references.citation: Genome Res. 2006 Dec;16(12):1585-95
references.pmid: 17053090
references.citation: Genome Res. 2007 Nov;17(11):1550-61
references.pmid: 17908821
references.citation: Mol Cell Biol. 2010 Jun;30(12):2983-95
references.pmid: 20404092
references.citation: Cell Cycle. 2003 Nov-Dec;2(6):604-9
references.pmid: 14504477
references.citation: Nat Rev Mol Cell Biol. 2008 Sep;9(9):713-24
references.pmid: 18719710
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4459-64
references.pmid: 15753290
references.citation: Nature. 2009 Dec 17;462(7275):930-4
references.pmid: 20016602
references.citation: J Immunol. 1999 Dec 15;163(12):6631-9
references.pmid: 10586058
references.citation: Mol Cell Biol. 1996 Apr;16(4):1659-67
references.pmid: 8657141
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Mol Cell Biol. 2008 May;28(10):3127-38
references.pmid: 18347061
references.citation: Eur J Immunol. 2004 Jul;34(7):1961-71
references.pmid: 15214044
references.citation: Mol Cell Proteomics. 2013 May;12(5):1087-98
references.pmid: 23297349
references.citation: J Biol Chem. 2001 Dec 7;276(49):46132-41
references.pmid: 11560924
references.citation: Cell Cycle. 2008 Dec 15;7(24):3915-27
references.pmid: 19066456
references.citation: Nature. 2008 Sep 25;455(7212):552-6
references.pmid: 18794899
references.citation: Mol Cell. 2007 Jul 6;27(1):107-19
references.pmid: 17612494
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W393-6
references.pmid: 15980497
references.citation: Nat Rev Cancer. 2009 Nov;9(11):785-97
references.pmid: 19851314
references.citation: Genome Res. 2008 Nov;18(11):1763-77
references.pmid: 18836037
references.citation: Mol Cell Biol. 2000 Feb;20(3):1008-20
references.pmid: 10629058
references.citation: Genes Dev. 2001 Feb 1;15(3):267-85
references.pmid: 11159908
references.citation: Cell. 1994 Jun 3;77(5):713-25
references.pmid: 8205620
references.citation: Oncogene. 2010 Oct 14;29(41):5579-90
references.pmid: 20676136
references.citation: Mol Cell. 2007 May 25;26(4):539-51
references.pmid: 17531812