The Epstein-Barr virus replication and transcription activator, Rta/BRLF1, induces cellular senescence in epithelial cells
Open accessAbstract
Epstein-Barr Virus (EBV) replication and transcription activator (Rta/BRLF1) is an immediate-early transcription factor that controls the conversion of the latent viral genome into one undergoing lytic replication. By using a doxycycline-inducible expression system, the present study demonstrates that EBV Rta efficiently elicits growth arrest in the human epithelial cell line HEK293. In cells arrested by EBV Rta, the expression of p21 (CDKN1A), p27 (CDKN1B) and cyclin E were increased. In contrast, the levels of cyclin D1, CDK4 and CDK6 were sharply decreased. Activation of the host cell DNA damage response (DDR), indicated by the increasing phosphorylation of H2AX and p53 Ser15, was observed on day 3 and day 5 after EBV Rta expression, respectively. Finally, EBV Rta arrested cells exhibited strong senescence-associated beta-galactosidase staining on day 10 after doxycycline induction. Together, these results indicate that, in addition to triggering viral lytic replication in epithelial cells, EBV Rta concurrently initiates a cellular senescence program that was previously undocumented. This finding, showing Rta may be centrally involved in inducing a host cell state amenable to efficient viral reproduction, in addition to its previously characterized regulation of viral transcription, provides new perspectives in understanding EBV pathogenesis.
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EBV infection induces expression of p16INK4a or p21CIP1, which act as a primary host defence against virus propagation, and EBV-positive cells losing expression of these mediators are selected for in manifest chronic infection.
“EBV infection has long been known to induce the expression of central signalling mediators of the senescence response such as p16INK4a or p21CIP1. These proteins act as a primary host defence against virus propagation, and EBV-positive cells losing expression of these mediators subsequently get selected for in manifest chronic infection187,188.”
From COVID-19 and cellular senescence (2023) · cites this paper as [188]
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- Authors
- Chen, Y.-L., Chen, Y.-J., Tsai, W.-H., Ko, Y.-C., Chen, J.-Y., & Lin, S.-F.
- Affiliations
- National Health Research Institutes (TW)
- Corresponding author
- Lin, Su-Fang
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2009-01
- Volume
- 8
- Issue
- 1
- Pages
- 58-65
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2079928282
- Cited by
- 37
- References
- 50
- Citations by year
- 2026: 3 · 2024: 3 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health Research Institutes
- Topics
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- Epstein-Barr virus, cellular senescence, epithelial cells, growth arrest, p21, p27, cyclin E, cyclin D1, CDK4, CDK6, DNA damage response, H2AX phosphorylation, p53 Ser15 phosphorylation, senescence-associated β-galactosidase, viral pathogenesis
- MeSH terms
- beta-Galactosidase, Cell Line, Doxycycline, Epithelial Cells, Herpesvirus 4, Human, Humans, Kinetics, Luciferases, Nasopharynx, Tetracycline, Virus Replication, Trans-Activators, G1 Phase, Cellular Senescence, Immediate-Early Proteins, Cell Proliferation, Protein Stability
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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