{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n E4F1 is a multifunctional protein that plays pivotal roles in the regulation of cell cycle progression, genome integrity, DNA repair, and cellular metabolism. On one level, E4F1 functions as an atypical ubiquitin E3 ligase that modifies p53 through oligo‐ubiquitylation at a distinct hinge region, thereby promoting a p53‐dependent transcriptional program that favors cell cycle arrest over apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, E4F1 (often characterized as its full‐length form, p120(E4F1)) interacts with transcriptional regulators such as HMGA2 to influence the transcriptional control of genes involved in cell cycle progression (for example, by modulating cyclin A promoter activity), thus contributing to proper cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in transcriptional regulation, E4F1 is essential for normal embryonic development and mitotic progression; its complete inactivation leads to peri‐implantation lethality and is associated with defects in spindle formation and chromosome segregation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In adult tissues, conditional deletion of E4F1 in skin results in disrupted epithelial homeostasis and epidermal stem cell exhaustion, an effect that is linked to the deregulation of the BMI1–Arf–p53 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In transformed myeloid cells, loss of E4F1 compromises mitochondrial function, leading to energy stress, an increase in reactive oxygen species, and a subsequent, selective cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, E4F1 is rapidly recruited to sites of DNA damage in a PARP‐dependent manner where it facilitates ATR/CHK1 signaling, DNA end resection, and homologous recombination by partnering with ATP‐dependent chromatin remodeling complexes such as SWI/SNF."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Consistent with its broad regulatory spectrum, E4F1 also transcriptionally controls key metabolic genes, including Dlat—a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase complex—thereby supporting pyruvate oxidation and ensuring proper metabolic flux required for tissue homeostasis, as observed in keratinocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies reveal E4F1 as an essential integrator of cell cycle checkpoints, stress responses, DNA repair processes, and metabolic homeostasis. Its diverse roles underscore its importance in both normal development and tumorigenesis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Laurent Le Cam, Laëtitia K Linares, Conception Paul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2006.09.031"}], "href": "https://doi.org/10.1016/j.cell.2006.09.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17110336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17110336"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Helen Rizos, Eve Diefenbach, Prerna Badhwar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M210978200"}], "href": "https://doi.org/10.1074/jbc.M210978200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12446718"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12446718"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Michela A Tessari, Monica Gostissa, Sandro Altamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.23.24.9104-9116.2003"}], "href": "https://doi.org/10.1128/MCB.23.24.9104-9116.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14645522"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14645522"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Laurent Le Cam, Matthieu Lacroix, Maria A Ciemerych, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E4F protein is required for mitotic progression during embryonic cell cycles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.24.14.6467-6475.2004"}], "href": "https://doi.org/10.1128/MCB.24.14.6467-6475.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15226446"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15226446"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Matthieu Lacroix, Julie Caramel, Perrine Goguet-Rubio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1010167107"}], "href": "https://doi.org/10.1073/pnas.1010167107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21088222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21088222"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elodie Hatchi, Genevieve Rodier, Matthieu Lacroix, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20101995"}], "href": "https://doi.org/10.1084/jem.20101995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21708927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21708927"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Céline Moison, Jalila Chagraoui, Marie-Christine Caron, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zinc finger protein E4F1 cooperates with PARP-1 and BRG1 to promote DNA double-strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2019408118"}], "href": "https://doi.org/10.1073/pnas.2019408118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33692124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33692124"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Perrine Goguet-Rubio, Berfin Seyran, Laurie Gayte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1602751113"}], "href": "https://doi.org/10.1073/pnas.1602751113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27621431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27621431"}]}]}]}