E2F

E2F stands for family of transcription factors (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 mammalian cells. E2Fs as TFs bind to the TTTCGCGC consensus binding site in the target promoter sequence.

Structure
Homo sapiens E2F1 mRNA or E2F1 protein sequences from NCBI protein and nucleotide database.

Role in the cell cycle
E2F family member play a major role during the G1/S transition in the mammalian cell cycle (see KEGG cell cycle pathway). Among E2F transcriptional targets are cyclins, cdks, checkpoints regulators, DNA repair and replication proteins.

E2F/pRb complexes
The 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 E2F1-3a genes follows upon the growth factor stimulation and the subsequent phosphorylation of the E2F inhibitor 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 E2F1-3a, pRb can directly repress E2F1-3a 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 a repressors independent 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, CDK2, MYB, E2F1,2,3, TFDP1, CDC25A
 * Negative regulators: E2F7, RB1, TP107, TP21
 * Checkpoints: TP53, BRCA1,2, BUB1
 * Apoptosis: TP73, APAF1, CASP3,7,8, MAP3K5,14
 * Nucleotide synthesis: thymidine kinase (tk), thymidylate synthase (ts), DHFR
 * DNA repair: BARD1, RAD51, UNG1,2
 * DNA replication: PCNA, histone H2A, DNA pol$$\alpha$$ and $$\delta$$, RPA1,2,3, CDC6, MCM2,3,4,5,6,7