E2F1 (E2F transcription factor 1)

	Schematic representation of human E2F1, depicting conserved domains and post-translational modification sites (see description for details).
Description	Length: 437 aa, molecular weight: 46920 Da. The protein contains a number of conserved domains, including a cyclin A binding domain (aa 67-108); a nuclear localization signal (NLS, aa 85-91); a helix-loop-helix DNA binding domain (aa 120-191); a heptad repeat (aa 201-243), which mediates homo/hetero dimerization; a marked box (245-317), which is implicated in the E2F/DP and E2F/E4 ORF 6/7 interaction, and is also essential for the apoptotic activity of E2F1; and a transactivation domain (aa 368-437) containing the pRB binding domain (aa 409-426). The E2F1 protein molecule is subject to a number of post-translational modifications, including phosphorylation by cyclin D / CDK4 / CDK6 at serine residues 332 and 337, which stabilizes E2F1 and prevents its binding to pRB regardless of its phosphorylation status; acetylation of lysine residues 117, 120, and 125 by the factor acetyltransferase (FAT) complex CBP/p/CAF, which enhances DNA binding and stabilizes E2F1 further; phosphorylation by cyclin A / CDK2 at serine residue 375, which reduces DNA binding; and phosphorylation at serine residues 31 and 364 by ATM/ATR and CHK2 kinases, respectively, in response to DNA damage, which stabilizes E2F1 and promotes its apoptotic activity.
Expression	E2F1 is expressed in all actively proliferating tissues in a cell-cycle specific manner. It is expressed mainly at late G1 and G1/S transition, and its mRNA is absent or low during the rest of the cell cycle.
Localisation	E2F1 is constitutively nuclear, due to a Nuclear Localization Signal (NLS) located around aa 90.
Function	E2F1 represents a controversial player in cell cycle control, exhibiting a dual behavior, sometimes acting as a tumor-suppressor and others as an oncogene. E2F1 exerts transcriptional control over the cell cycle, induces apoptosis via distinct pathways, and participates in DNA damage response and checkpoint. Transcriptional control E2F1 belongs to the E2F family of transcription factors, coordinating the expression of key genes involved in cell cycle regulation and progression. It is active during the G1 to S transition, and thus its target genes, which include regulatory elements of the cell cycle, such as CDC2, CDC25A and cyclin E, and essential components of DNA replication machinery, including DHFR, and DNA polymerase alpha, are expressed in a cell cycle dependent manner (i.e. only in late G1 and early S phase of the cell cycle). E2F1 recognizes and binds to specific DNA sequences (5'-TTTSSCGS-3', where S = C/G) that lie within the promoter of target genes, in the form of functional heterodimers with members of the DP family of transcription factors. Apoptosis E2F1 can induce apoptosis via distinct P53-dependent and independent pathways. The P53-independent pathways involve the p53 homolog P73 and APAF1, which are both transcriptionally controlled by E2F1. Transcriptional activation of P73 by E2F1 may lead to the activation of P53-responsive target genes, while induction of APAF1 transcription leads to activation of the caspase cascade. Ultimately, both pathways lead to cell death by apoptosis. Moreover, E2F1 is implicated in the upregulation of the pro-apoptotic members of the BCL2 family, but also in the downregulation of anti-apoptotic signals, by inhibiting NF-kB activity, thereby enhancing also apoptosis. There are many pathways linking E2F1 to P53-dependent apoptosis. The main mechanism involves direct transcriptional activation of the p14ARF tumor suppressor gene by E2F1. ARF sequesters MDM2 away from P53, leading consequently to P53 stabilization and activation. Nevertheless, ARF overexpression may lead to E2F1 downregulation, as ARF targets the latter for proteasomal degradation through p45skp2-dependent pathways. On the other hand, E2F1 can induce P53-dependent apoptosis in the absence of ARF. For instance, E2F1 can interact directly with P53 through the cyclin A-binding domain of E2F1, enhancing its apoptotic activity in response to DNA damage. Additionally, some reports argue that E2F1 uses the ATM pathway in order to activate both P53 and CHK2. Finally, E2F1 can augment the apoptotic capacity of P53 by enhancing the transcription of pro-apoptotic P53 cofactors such as P53-ASPP1, ASPP2, JMY and TP53INP1. DNA Damage Response In response to DNA damage, E2F1 is upregulated through phosporylation-mediated stabilization. E2F1 is phosphorylated at S31 by ATM/ATR kinases and at S364 by CHK2 kinase, which are all integral components of the DNA damage signaling pathway. These phosphorylations interfere with the ARF/SKP2- and MDM2-dependent degradation of E2F1, thus stabilizing the latter by decreasing its turnover rate. In response to IR or other agents that cause DNA double strand breaks, phosphorylation by ATM/ATR seems to prime E2F1 for acetylation at specific lysine residues. These acetylations are a prerequisite for the targeting of the P73 gene promoter by E2F1, which ultimately leads to apoptosis (see above paragraph). UV radiation does not trigger E2F1 acetylation and apoptosis. Instead, E2F1 seems to play a role in DNA repair and cell survival, either directly at the sites of DNA repair or through modulation of DNA repair genes that are under its transcriptional control.
Homology	Shares lesser or greater homology with other members of the E2F family (E2F2, E2F3, E2F4, E2F5, E2F6) and with the DP family of transcription factors ( DP1, DP2).

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