Expression level is a key determinant of E2F1-mediated cell fate

Igor Shats, Michael Deng, Adam Davidovich, Carolyn Zhang, Jungeun S. Kwon, Dinesh Manandhar, Raluca Gordân, Guang Yao, Lingchong You

Research output: Research - peer-reviewArticle

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Abstract

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.

LanguageEnglish (US)
Pages626-637
Number of pages12
JournalCell Death and Differentiation
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2017

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Neoplasms
Apoptosis
Phenotype
Population
G2 Phase Cell Cycle Checkpoints
Single-Cell Analysis
RNA Sequence Analysis
cdc Genes
Proteasome Inhibitors
Post Translational Protein Processing
Lung Neoplasms
Cell Cycle
Up-Regulation
Pressure
Cell Line
Polymerase Chain Reaction
Growth
Genes
Therapeutics
MLN2238

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Shats, I., Deng, M., Davidovich, A., Zhang, C., Kwon, J. S., Manandhar, D., ... You, L. (2017). Expression level is a key determinant of E2F1-mediated cell fate. Cell Death and Differentiation, 24(4), 626-637. DOI: 10.1038/cdd.2017.12

Expression level is a key determinant of E2F1-mediated cell fate. / Shats, Igor; Deng, Michael; Davidovich, Adam; Zhang, Carolyn; Kwon, Jungeun S.; Manandhar, Dinesh; Gordân, Raluca; Yao, Guang; You, Lingchong.

In: Cell Death and Differentiation, Vol. 24, No. 4, 01.04.2017, p. 626-637.

Research output: Research - peer-reviewArticle

Shats, I, Deng, M, Davidovich, A, Zhang, C, Kwon, JS, Manandhar, D, Gordân, R, Yao, G & You, L 2017, 'Expression level is a key determinant of E2F1-mediated cell fate' Cell Death and Differentiation, vol 24, no. 4, pp. 626-637. DOI: 10.1038/cdd.2017.12
Shats I, Deng M, Davidovich A, Zhang C, Kwon JS, Manandhar D et al. Expression level is a key determinant of E2F1-mediated cell fate. Cell Death and Differentiation. 2017 Apr 1;24(4):626-637. Available from, DOI: 10.1038/cdd.2017.12
Shats, Igor ; Deng, Michael ; Davidovich, Adam ; Zhang, Carolyn ; Kwon, Jungeun S. ; Manandhar, Dinesh ; Gordân, Raluca ; Yao, Guang ; You, Lingchong. / Expression level is a key determinant of E2F1-mediated cell fate. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 4. pp. 626-637
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