E2F 2228126 226002238 2008-07-16T11:50:16Z Boghog2 2428506 reformatted figure and legend as table '''E2F''' is a group of genes that codifies a family of [[transcription factor]]s (TF) in higher [[eukaryotes]]. Three of them are activators: E2F1,2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the [[cell cycle]] regulation and synthesis of DNA in [[mammal|mammalian]] cells. E2Fs as TFs bind to the TTTCGCGC consensus [[binding site]] in the target [[promoter]] sequence. ==E2F family== Schematic diagram of the [[peptide sequence|amino acid sequence]]s of E2F family members ([[N-terminus]] to the right, [[C-terminus]] to the left) highlighting the relative locations of functional [[protein domain|domains]] within each member: {| class="wikitable" |- ! Family members ! Legend |- | [[Image:E2F_family_member.png|400px]] | <br /> * '''cyc A''' - [[Cyclin A]] binding domain<br /> * '''cyc A''' - [[Cyclin A]] binding domain<br /> * '''DNA''' - DNA-binding domain<br /> * '''DP1,2''' - domain for dimerization with DP1,2<br /> * '''TA''' - transcriptional activation domain<br /> * '''PB''' - pocket protein binding domain |} ==Genes== Homo sapiens [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_005225.1 E2F1 mRNA] or [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=12669911 E2F1 protein] sequences from [[NCBI]] protein and nucleotide database. ==Structure== [[X-ray crystallography|X-ray crystallographic]] analysis has shown that the E2F family of transcription factors has a [[protein_structure#Tertiary_structure|fold]] similar to the [[winged-helix transcription factors|winged-helix]] [[DNA-binding domain|DNA-binding motif]].<ref name="pmid10090723">{{cite journal | author = Zheng N, Fraenkel E, Pabo CO, Pavletich NP | title = Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP | journal = Genes Dev. | volume = 13 | issue = 6 | pages = 666–74 | year = 1999 | pmid = 10090723 | doi = 10.1101/gad.13.6.666 | url = | issn = }}</ref> ==Role in the cell cycle== E2F family member play a major role during the G1/S transition in the mammalian [[cell cycle]] (see [http://www.genome.jp/dbget-bin/show_pathway?hsa04110+1869 KEGG cell cycle pathway]). Among E2F transcriptional targets are [[cyclin]]s, [[Cyclin-dependent kinase|cdk]]s, checkpoints regulators, [[DNA repair]] and replication proteins. ==E2F/pRb complexes== The [[Retinoblastoma protein|Rb tumour suppressor protein]] (pRb) binds to the E2F-1 transcription factor preventing it from interacting with the cells transcription machinery. In the absence of pRb, E2F-1 (along with its binding partner DP-1) mediates the trans-activation of E2F-1 target genes that facilitate the G1/S transition and S-phase. E2F target genes encode proteins involved in DNA replication (for example DNA polymerase, thymidine kinase (TK), dihydrofolate reductase (DHFR) and cdc6), chromosomal replication (replication origin-binding protein HsOrc1 and MCM 5). When cells are not proliferating, E2F DNA binding sites contribute to transcriptional repression. In vivo footprinting experiments obtained on [[Cdc2]] and B-myb promoters demonstrated E2F DNA binding site occupation during G0 and early G1, when E2F is in transcriptional repressive complexes with the pocket proteins. === Activators: E2F1, E2F2, E2F3a === Activators are maximally expressed late in G1 and can be found in association with E2F regulated promoters during the G1/S transition. The activation of E2F-3a genes follows upon the [[growth factor]] stimulation and the subsequent [[phosphorylation]] of the E2F inhibitor Retinoblastoma protein, [[Retinoblastoma protein|pRB]]. The [[phosphorylation]] of pRB is initiated by Cyclin D/cdk4,6 complex and continued by Cyclin E/cdk2. Cyclin D/cdk4,6 itself is activated by the [[MAPK]] signaling pathway. When bound to E2F-3a, pRb can directly repress E2F-3a target genes by recruiting chromatin remodeling complexes and histone modifying activities (e.g. histone deacetylase, [[HDAC]]) to the promoter. === Inhibitors: E2F3b, E2F4, E2F5, E2F6, E2F7, E2F8 === * E2F3b, E2F4, E2F5 are expressed in quiescent cells and can be found associated with E2F-binding elements on E2F-target promoters during G0-phase. E2F-4 and 5 preferentially bind to p107/p130. * E2F-6 acts as a transcriptional repressor, but through a distinct, pocket protein independent manner. E2F-6 mediates repression by direct binding to [[polycomb-group proteins]] or via the formation of a large multimeric complex containing Mga and Max proteins. * E2F7 and E2F8 proteins can function as repressors independently of DP interaction. They are unique in having a duplicated conserved E2F-like DNA-binding domain and in lacking a DP1,2-dimerization domain. The exact mechanism of mediating repression is not yet understood. ==Transcriptional targets== * Cell cycle: CCNA1,2, CCND1,2, [[Cyclin-dependent kinase|CDK2]], MYB, E2F1,2,3, TFDP1, CDC25A * Negative regulators: E2F7, [[Rb|RB1]], TP107, TP21 * Checkpoints: [[TP53]], [[BRCA1]],2, BUB1 * Apoptosis: TP73, APAF1, [[Caspase|CASP3]],7,8, MAP3K5,14 * Nucleotide synthesis: [[thymidine kinase]] (tk), thymidylate synthase (ts), [[Dihydrofolate reductase|DHFR]] * DNA repair: BARD1, RAD51, UNG1,2, FANCA, FANCC, FANCJ * DNA replication: [[PCNA]], [[histone]] H2A, [[DNA polymerase|DNA pol]]<math>\alpha</math> and <math>\delta</math>, RPA1,2,3, CDC6, MCM2,3,4,5,6,7 <ref name="pmid15838516">{{cite journal | author = Cobrinik D | title = Pocket proteins and cell cycle control | journal = Oncogene | volume = 24 | issue = 17 | pages = 2796–809 | year = 2005 | pmid = 15838516 | doi = 10.1038/sj.onc.1208619 | issn = }}</ref> <ref name="pmid15722552">{{cite journal | author = Maiti B, Li J, de Bruin A, Gordon F, Timmers C, Opavsky R, Patil K, Tuttle J, Cleghorn W, Leone G | title = Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation | journal = J. Biol. Chem. | volume = 280 | issue = 18 | pages = 18211–20 | year = 2005 | pmid = 15722552 | doi = 10.1074/jbc.M501410200 | issn = }}</ref> <ref name="pmid12004135">{{cite journal | author = Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y | title = A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells | journal = Science | volume = 296 | issue = 5570 | pages = 1132–6 | year = 2002 | pmid = 12004135 | doi = 10.1126/science.1069861 | issn = }}</ref> <ref name="pmid8524257">{{cite journal | author = Tommasi S, Pfeifer GP | title = In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression | journal = Mol. Cell. Biol. | volume = 15 | issue = 12 | pages = 6901–13 | year = 1995 | pmid = 8524257 | doi = | issn = | url = http://mcb.asm.org/cgi/content/abstract/15/12/6901 | format = abstract }}</ref> <ref name="pmid8599118">{{cite journal | author = Zwicker J, Liu N, Engeland K, Lucibello FC, Müller R | title = Cell cycle regulation of E2F site occupation in vivo | journal = Science | volume = 271 | issue = 5255 | pages = 1595–7 | year = 1996 | pmid = 8599118 | doi = 10.1126/science.271.5255.1595 | issn = }}</ref> <ref name="Tategu">{{cite journal | author = Tategu M, Arauchi T,Tanaka R,Nakagawa H, Yoshida K | title = Systems Biology-Based Identifi cation of Crosstalk between E2F Transcription Factors and the Fanconi Anemia Pathway | journal = Gene Regulation and Systems Biology | volume = 1 | issue = 1 | pages = 1–7 | year = 2007 | pmid = | doi = | issn = | url = http://la-press.com/article.php?article_id=219 }}</ref> ==References== {{Reflist|2}} ==External links== * {{MeshName|E2F+Transcription+Factors}} {{Transcription factors|g3}} {{Cell cycle proteins}} [[Category:Cell cycle]] [[Category:Transcription factors]] [[it:E2F]] [[pl:E2F]]