Expression level is a key determinant of E2F1-mediated cell fate
| العنوان: | Expression level is a key determinant of E2F1-mediated cell fate |
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| المؤلفون: | Michael Deng, Raluca Gordân, Igor Shats, Dinesh Manandhar, Lingchong You, Jungeun Sarah Kwon, Guang Yao, Carolyn Zhang, Adam Davidovich |
| المصدر: | Cell Death & Differentiation. 24:626-637 |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Boron Compounds, 0301 basic medicine, endocrine system, Cell cycle checkpoint, Cell, Population, Glycine, Apoptosis, Biology, Cell fate determination, Time-Lapse Imaging, Histones, 03 medical and health sciences, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Humans, E2F, education, Molecular Biology, Mitotic cell cycle arrest, Original Paper, education.field_of_study, Bcl-2-Like Protein 11, Cell Cycle Checkpoints, Cell Biology, HCT116 Cells, Cell biology, Tamoxifen, Apoptotic Protease-Activating Factor 1, 030104 developmental biology, medicine.anatomical_structure, Proteasome inhibitor, biological phenomena, cell phenomena, and immunity, Signal transduction, Apoptosis Regulatory Proteins, E2F1 Transcription Factor, medicine.drug |
| الوصف: | The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation. In contrast, the importance of the expression levels of E2F1 itself in dictating the downstream phenotypes has not been rigorously studied, partly due to the limited resolution of traditional population-level measurements. Here, through single-cell quantitative analysis, we demonstrate that E2F1 expression levels have a critical role in determining the fate of individual cells. Low levels of exogenous E2F1 promote proliferation, moderate levels induce G1, G2 and mitotic cell cycle arrest, and very high levels promote apoptosis. These multiple anti-proliferative mechanisms result in a strong selection pressure leading to rapid elimination of E2F1-overexpressing cells from the population. RNA-sequencing and RT-PCR revealed that low levels of E2F1 are sufficient to induce numerous cell cycle-promoting genes, intermediate levels induce growth arrest genes (i.e., p18, p19 and p27), whereas higher levels are necessary to induce key apoptotic E2F1 targets APAF1, PUMA, HRK and BIM. Finally, treatment of a lung cancer cell line with a proteasome inhibitor, MLN2238, resulted in an E2F1-dependent mitotic arrest and apoptosis, confirming the role of endogenous E2F1 levels in these phenotypes. The strong anti-proliferative activity of moderately overexpressed E2F1 in multiple cancer types suggests that targeting E2F1 for upregulation may represent an attractive therapeutic strategy in cancer. |
| تدمد: | 1476-5403 1350-9047 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c638364a8615611e0782cc4cc6cde68 https://doi.org/10.1038/cdd.2017.12 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9c638364a8615611e0782cc4cc6cde68 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765403 13509047 |
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