ATR controls the p21WAF1/Cip1 protein up‐regulation and apoptosis in response to low UV fluences
Abstract
The universal cyclin‐dependent kinase inhibitor p21 WAF1/Cip1 promotes cell cycle arrest and inhibits apoptosis in response to UV‐induced DNA damage. Since the protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21 WAF1/Cip1 expression in response to UVC radiation. We have shown that p21 WAF1/Cip1 is up‐regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up‐regulation is ATR‐dependent. In fact, in ATR‐deficient or caffeine‐treated cells UV light rather down‐regulated the p21 WAF1/Cip1 protein through SKP2‐dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21 WAF1/Cip1 protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR protein kinase up‐regulates p21 WAF1/Cip1 and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.
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p21 is degraded upon lower doses of UV irradiation even though this lower level does not affect the cell cycle checkpoint.
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [59]
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- Authors
- Al‐Khalaf, H. H., Hendrayani, S., & Aboussekhra, A.
- Affiliations
- King Abdulaziz City for Science and Technology (SA)
- King Faisal Specialist Hospital & Research Centre (SA)
- Corresponding author
- Aboussekhra, Abdelilah
- Venue
- Molecular Carcinogenesis
- Publisher
- Wiley
- Published
- 2011-10-04
- Volume
- 51
- Issue
- 12
- Pages
- 930-938
- ISSN
- 0899-1987 (ISSN-L)
- 1098-2744
- OpenAlex
- W2076776668
- Cited by
- 13
- References
- 45
- Citations by year
- 2021: 1 · 2020: 2 · 2016: 2 · 2014: 1 · 2013: 4 · 2012: 3
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Keywords
- ATR kinase, p21, UV-induced DNA damage, UV-C radiation, apoptosis, Skp2, ubiquitination, proteasomal degradation, protein stability, caspase-3, PARP cleavage, Bax, Bak, cell cycle arrest, human fibroblasts, epithelial cells
- MeSH terms
- Cell Cycle, Dose-Response Relationship, Radiation, Electrophoresis, Polyacrylamide Gel, Humans, Ultraviolet Rays, Blotting, Western, Up-Regulation, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p21, Ubiquitination, Ataxia Telangiectasia Mutated Proteins
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