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Review
. 2015 Jan 30;2(1):e970480.
doi: 10.4161/23723548.2014.970480. eCollection 2015 Jan-Mar.

To live or let die - complexity within the E2F1 pathway

A Poppy Roworth  1 , Fatemeh Ghari  1 , Nicholas B La Thangue  1
Affiliations
Review

To live or let die - complexity within the E2F1 pathway

A Poppy Roworth et al. Mol Cell Oncol. .

Abstract

The E2F1 transcription factor is a recognized regulator of the cell cycle as well as a potent mediator of DNA damage-induced apoptosis and the checkpoint response. Understanding the diverse and seemingly dichotomous functions of E2F1 activity has been the focus of extensive ongoing research. Although the E2F pathway is frequently deregulated in cancer, the contributions of E2F1 itself to tumorigenesis, as a promoter of proliferation or cell death, are far from understood. In this review we aim to provide an update on our current understanding of E2F1, with particular insight into its novel interaction partners and post-translational modifications, as a means to explaining its diverse functional complexity.

Keywords: DNA damage response; E2F1; apoptosis; cancer; cell cycle; epigenetics.

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Figures

Figure 1 (See previous page).
Figure 1 (See previous page).
Cell cycle-dependent regulation of E2F1. (A) It is hypothesized that the E2F1–DP1 heterodimer can mediate proliferation versus apoptosis depending on the cellular levels of E2F1 and its post-translational modifications. Upon mitogenic stimulation binding of pRB is reduced and E2F1 can enhance transcription of cell cycle target genes. However, after DNA damage E2F1 is stabilized by various post-translational modifications and this results in transcription of pro-apoptotic target genes. (B) During early G1 phase E2F1 is maintained in an inactive state via interaction with pRB; this blocks the transcriptional activation domain of E2F1 and furthermore recruits HDACs and the SWI/SNF complex to actively suppress transcription from E2F1 target genes. Upon mitogenic stimulation, cyclin D levels are induced; cyclin D forms a complex with CDK4–6 that phosphorylates pRB and relieves the inhibition from HDACs and the SWI/SNF complex. This allows transcription of several E2F1 target genes, including cyclin E, to proceed. As cyclin E levels accumulate and cells progress toward late G1, the CDK2-cyclin E complex is formed, which hyperphosphorylates pRB to completely dissociate it from E2F1. Subsequently, transcription of several other E2F1 target genes is induced, including cyclin A and DNA replication genes. During late S phase E2F1 is inactivated, the DP1 binding partner is targeted for phosphorylation by CDK2–cyclin A, and E2F1 targeted for degradation by SKP2 and transcriptional repression by E2F7/8.
Figure 2.
Figure 2.
DNA damage-dependent regulation of E2F1. (A) E2F1 is modified following DNA damage resulting in cellular accumulation and upregulation of apoptotic E2F1 target genes and repression of survival pathways. This results in transcription of proapoptotic target genes, which largely affect the intrinsic apoptotic signaling pathway at the mitochondria or, in the case of p53 and p73, increase apoptotic gene transcription to amplify these effects. The intrinsic p53-dependent and -independent pathways that culminate in caspase-3 activation and cell death are shown. Blue describes nuclear events, yellow portrays events at the mitochondrial outer membrane, and green depicts cytoplasmic events. Dashed lines represent steps that have been omitted. (B) The main domains of E2F1 include the nuclear localization signal (NLS), cyclin A binding domain (CycA), the DNA binding domain (DBD), the DP binding domain (DP), the marked box (MB), and the transactivation domain (TAD), which also contains the pRB binding domain (RB). The main modifications of E2F1, the respective residues, and the responsible enzyme are outlined in the figure. Encircled (P) signifies phosphorylation, (Me) methylation, (Ac) acetylation, and (Nd) NEDDylation.
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References

    1. DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci 1997; 94:7245-50; PMID:9207076; http://dx.doi.org/10.1073/pnas.94.14.7245 - DOI - PMC - PubMed
    1. Black EP, Hallstrom T, Dressman HK, West M, Nevins JR. Distinctions in the specificity of E2F function revealed by gene expression signatures. Proc Natl Acad Sci 2005; 102:15948-53; PMID:16249342; http://dx.doi.org/10.1073/pnas.0504300102 - DOI - PMC - PubMed
    1. Ingram L, Munro S, Coutts AS, La Thangue NB. E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit. Cell Death Differ 2011; 18:122-32; PMID:20559320; http://dx.doi.org/10.1038/cdd.2010.70 - DOI - PMC - PubMed
    1. Narita M, Nunez S, Heard E, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113:703-16; PMID:12809602; http://dx.doi.org/10.1016/S0092-8674(03)00401-X - DOI - PubMed
    1. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K. The retinoblastoma protein binds to a family of E2F transcription factors. Mol Cell Biol 1993; 13:7813-25; PMID:8246996 - PMC - PubMed