title: Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1.
abstract: 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.
authors.affiliation: IUF-Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Frauenstein
authors.forename: U
authors.initials: U
authors.lastname: Sydlik
authors.forename: J
authors.initials: J
authors.lastname: Tigges
authors.forename: M
authors.initials: M
authors.lastname: Majora
authors.forename: C
authors.initials: C
authors.lastname: Wiek
authors.forename: H
authors.initials: H
authors.lastname: Hanenberg
authors.forename: J
authors.initials: J
authors.lastname: Abel
authors.forename: C
authors.initials: C
authors.lastname: Esser
authors.forename: E
authors.initials: E
authors.lastname: Fritsche
authors.forename: J
authors.initials: J
authors.lastname: Krutmann
authors.forename: T
authors.initials: T
authors.lastname: Haarmann-Stemmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071877:Checkpoint Kinase 1; D050687:E2F1 Transcription Factor; D011494:Protein Kinases; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C000605867:CHEK1 protein, human; C000605869:Chek1 protein, mouse
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