Early growth response 2 (EGR2) is a novel regulator of the senescence programme
Eleanor J Tyler1, Ana Gutierrez Del Arroyo2, Bethany K Hughes1
1Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Abstract:
Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down-regulates p16 levels and increases the pool of p16- p21- 'reversed' cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.
Insights
Early growth response 2 (EGR2) is a novel regulator of cellular senescence. This transcription factor activates key senescence pathways, offering a new marker for ageing and related diseases.
Area of Science:
- Cellular Biology
- Molecular Biology
- Gerontology
Background:
- Cellular senescence, a stable growth arrest, is crucial in aging and age-related diseases.
- The INK4/ARF locus is vital for senescence, but its transcriptional regulators are not fully understood.
Purpose of the Study:
- To identify novel regulators of the p16/pRB and ARF/p53/p21 senescence pathways.
- To investigate the role of EGR2 in cellular senescence.
Main Methods:
- siRNA screening in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs).
- Analysis of EGR2 expression, promoter binding, and effects on senescence markers.
- EGR2 overexpression studies.
Main Results:
- EGR2 was identified as a novel regulator of senescence, upregulated during the process.
- EGR2 ablation transiently reversed the senescent phenotype in DS HMECs and HMFs.
- EGR2 directly activates the ARF and p16 promoters, and its loss down-regulates p16.
Conclusions:
- EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence.
- EGR2 functions as a novel marker and regulator of cellular senescence.
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