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Published on: May 1, 2020
E2F1 regulates autophagy and the transcription of autophagy genes
S Polager1, M Ofir, D Ginsberg
1The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, Israel.
Abstract:
The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity that can induce both proliferation and cell death. Although the role of E2F in apoptosis is well characterized, little is known regarding its putative participation in other cell death pathways. We show here that activation of E2F1 upregulates the expression of four autophagy genes-microtubule-associated protein-1 light chain-3 (LC3), autophagy-related gene-1 (ATG1), ATG5 and damage-regulated autophagy modulator (DRAM). E2F1-mediated induction of LC3, ATG1 and DRAM is direct and indeed, endogenous E2F1 can be found bound to regions encompassing the promoters of these genes. Regulation of ATG5 by E2F1 is indirect. Importantly, we demonstrate that E2F1 activation enhances autophagy and conversely, reducing endogenous E2F1 expression inhibits DNA damage-induced autophagy. These studies identify E2F1 as a transcriptional regulator of autophagy, and for the first time establish a role for E2F1 in DNA damage-induced autophagy.
Insights
The retinoblastoma pathway protein E2F1 directly upregulates autophagy genes, enhancing this cell survival process. This study reveals E2F1
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- The retinoblastoma pathway is frequently inactivated in human cancers, leading to dysregulated E2F transcription factor activity.
- While E2F's role in apoptosis is established, its involvement in other cell death mechanisms, like autophagy, remains unclear.
Purpose of the Study:
- To investigate the role of E2F1 in regulating autophagy.
- To determine if E2F1 influences DNA damage-induced autophagy.
Main Methods:
- Analysis of E2F1-mediated gene expression changes.
- Chromatin immunoprecipitation assays to assess E2F1 binding to gene promoters.
- Assessment of autophagy levels following E2F1 activation or inhibition.
Main Results:
- E2F1 activation upregulates the expression of key autophagy genes: microtubule-associated protein-1 light chain-3 (LC3), autophagy-related gene-1 (ATG1), and damage-regulated autophagy modulator (DRAM).
- E2F1 directly binds to the promoter regions of LC3, ATG1, and DRAM, indicating transcriptional regulation.
- E2F1 activation enhances autophagy, and reduced E2F1 levels inhibit DNA damage-induced autophagy.
Conclusions:
- E2F1 acts as a transcriptional regulator of autophagy.
- This study establishes a novel role for E2F1 in DNA damage-induced autophagy, linking the retinoblastoma pathway to this critical cellular process.
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