Early growth response 2 (EGR2) is a novel regulator of the senescence programme
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 06, 2021
- Source ID
- 10.1111/acel.13318
Entities
People
- Ana Gutierrez Del Arroyo
- Bethany K. Hughes
- Cleo L. Bishop
- Eleanor J. Tyler
- James C. Garbe
- Jim Koh
- Martha R Stampfer
- Michael P. Philpott
- Robert Lowe
- Ryan Wallis
Organizations
- Barts and The London School of Medicine and Dentistry
- Congressionally Directed Medical Research Programs
- Lawrence Berkeley National Laboratory
- Medical Research Council
- Queen Mary University of London
- United States Department of Energy
- University of California, San Francisco