Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1
Open accessAbstract
Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27(KIP1) and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer.
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β-actin (ACTB) was used as a control housekeeping gene because its gene expression is not affected by AHR ligation.
“We used β-actin (ACTB) as a control housekeeping gene, because its gene expression is not affected by AHR ligation [18,35].”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [35]
The Quantitative real-time PCR subsection of Materials and Methods (page unavailable) says gene expression was normalized to β-actin, supporting its use as a control. Our copy does not state or demonstrate that β-actin expression is unaffected by AHR ligation; the reported lack of response to an AHR agonist concerns E2F1 promoter activity, not β-actin. (LLM, conf=0.83)
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The E3 ligase Itch knockout mice show hyperproliferation and wound healing alteration
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Self-citation
- Authors
- Frauenstein, K., Sydlik, U., Tigges, J., Majora, M., Wiek, C., Hanenberg, H., Abel, J., Esser, C., Fritsche, E., Krutmann, J., & Haarmann-Stemmann, T.
- Affiliations
- Leibniz Institute of Environmental Medicine (DE)
- Heinrich Heine University Düsseldorf (DE)
- Venue
- Cell Death & Differentiation
- Published
- 2013-08-02
- Volume
- 20
- Issue
- 10
- Pages
- 1425-1434
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3770322
- OpenAlex
- W1979802104
- Cited by
- 56
- References
- 63
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 4
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SPP 1230)
- Bundesministerium für Bildung und Forschung
- Symrise
- Topics
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- aryl hydrocarbon receptor, E2F1, Chk1, keratinocytes, UVB-induced apoptosis, anti-apoptotic pathways, p27, CDK2, retinoblastoma protein, caspase-3 cleavage, photocarcinogenesis, AhR knockout mice, shRNA knockdown
- MeSH terms
- Checkpoint Kinase 1, Animals, Humans, Male, Protein Kinases, Transfection, Signal Transduction, Keratinocytes, Apoptosis, Receptors, Aryl Hydrocarbon, Mice, Knockout, E2F1 Transcription Factor, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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