Loss of Fas-Ligand Expression in Mouse Keratinocytes during UV Carcinogenesis

Ouhtit, Allal; Gorny, Alexander; Muller, HK; Hill, Laurie L.; Owen‐Schaub, Laurie B.; Ananthaswamy, Honnavara N.

doi:10.1016/s0002-9440(10)64836-5

Cited by 78 publications

(105 citation statements)

References 34 publications

(42 reference statements)

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“…TUNEL assay data indicated the absence of TUNEL-positive cells in mouse skin irradiated with UV light for 8 weeks. This was expected because we showed previously that chronic UV irradiation results in apoptosis resistance (Ouhtit et al, 2000a). However, TUNEL-positive cells were also absent in the epidermis of mice at all time points after UV irradiation discontinuation (data not shown), suggesting that decreased epidermal hyperplasia was not due to apoptosis.…”

Section: Timesupporting

confidence: 75%

“…We have previously shown that exposure of SKH-hr1 mice to chronic UV radiation induced SCCs (Ouhtit et al, 2000a). UV-signature CC-TT and C-T mutations in p53 codons 154-155, 175-176, and 270 or 275 were detected in epidermis as early as after 1 week of chronic UV irradiation (Ouhtit et al, 2000a).…”

Section: Introductionmentioning

confidence: 94%

“…UV-signature CC-TT and C-T mutations in p53 codons 154-155, 175-176, and 270 or 275 were detected in epidermis as early as after 1 week of chronic UV irradiation (Ouhtit et al, 2000a). These mutations were detected in the epidermis of 80% of mice irradiated for 4 weeks and 90% of mice irradiated for 8 weeks (Ouhtit et al, 2000a). The mice began to develop skin tumors after 8 weeks of chronic irradiation, and all mice developed multiple skin tumors, mostly SCCs, by week 25 of chronic UV irradiation.…”

Section: Introductionmentioning

confidence: 97%

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Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

et al. 2005

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Chronic exposure to ultraviolet (UV) radiation causes skin cancer in humans and mice. We have previously shown that in hairless SKH-hr1 mice, UVB-induced p53 mutations arise very early, well before tumor development. In this study, we investigated whether discontinuation of UVB exposure before the onset of skin tumors results in the disappearance of p53 mutations in the skin of hairless SKH-hr1 mice. Irradiation of mice at a dose of 2.5 kJ/m 2 three times a week for 8 weeks induced p53 mutations in the epidermal keratinocytes of 100% of the mice. UVB irradiation was discontinued after 8 weeks, but p53 mutations at most hotspot codons were still present even 22 weeks later. During that period, the percent of mice carrying p53 V154A/R155C , p53 H175H/H176Y , and p53 R275C mutant alleles remained at or near 100%, whereas the percentage of mice with p53 R270C mutation decreased by 45%. As expected, discontinuation of UVB after 8 weeks resulted in a delay in tumor development. A 100% of tumors carried p53 V154A/R155C mutant alleles, 76% carried p53 H175H/H176Y mutants, and 24 and 19% carried p53 R270C and p53 R275C mutants, respectively. These results suggest that different UVB-induced p53 mutants may provide different survival advantages to keratinocytes in the absence of further UVB exposure and that skin cancer development can be delayed but not prevented by avoidance of further exposure to UVB radiation.

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Section: Timesupporting

confidence: 75%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

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Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

et al. 2005

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“…These findings provided strong evidence that UVB triggers the CD95 apoptotic pathway by directly activating the CD95 receptor. In another study, Ouhtit et al 18 reported early (3 hours after acute UV exposure) up-regulation of Fas in the skin of hairless mice accompanied by increase in its ligand. However, prolonged overexpression of Fas and the loss of expression of the ligand were observed with chronic (weeks) UV irradiation.…”

Section: Discussionmentioning

confidence: 93%

“…Chronic exposure to sunlight (as evidenced by the presence of solar elastosis), up-regulates Fas expression, which extends up to the granular layer, similar to the experimental data. 12,18,19 With further sun-induced skin damage resulting in AK, which represents the earliest morphologic stage in development of skin carcinoma, there was marked down-regulation, or total loss of CD95 expression. This down-regulation was retained in invasive SCC.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD95 (Fas) in sun‐exposed human skin and cutaneous carcinomas

Filipowicz

Adegboyega

Sánchez

et al. 2002

Cancer

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BACKGROUNDCarcinomas of the skin are by far the most common human malignancies. Continuous exposure to ultraviolet (UV) light facilitates the development of precancerous lesions (actinic keratosis [AK]) that may progress to invasive squamous carcinomas. Apoptosis, triggered by the activation of CD95 (Fas), is one of the most important defense mechanisms against UV light–induced carcinogenesis in experimental models, but the dynamics of CD95 expression in patients with sun‐induced lesions are largely unknown.METHODSThe authors studied the expression of CD95 (Fas) in biopsy samples of normal skin (not exposed to sun) and compared it with chronically sun‐exposed skin (as evidenced by solar elastosis), AK, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), and keratoacanthomas (KA).RESULTSNormal skin keratinocytes expressed CD95 in cytoplasmic membranes and intercellular bridges in the basal layer. In chronically sun‐exposed keratinocytes (solar elastosis, no evidence of dysplasia), CD95 expression was up‐regulated and was observed throughout the entire thickness of the epidermis. However, in actinic keratosis there was a complete absence of Fas in approximately two‐thirds of the cases (8 of 12). In invasive SCC, CD95 was expressed focally and weakly only at the sites of contact with stromal lymphocytes. Keratoacanthomas consistently expressed CD95 at the interface with the inflammatory cells. No staining was observed in BCC.CONCLUSIONSCD95 (Fas) up‐regulation in chronically sun‐exposed keratinocytes indicates an important role in the control of sun‐induced damage. Further sun exposure results, however, in significant down‐regulation of this defense mechanism, proportional to the degree of dysplasia. Cancer 2002;94:814–9. © 2002 American Cancer Society.DOI 10.1002/cncr.10277

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Low‐dose UV‐radiation sensitizes keratinocytes to TRAIL‐induced apoptosis

Qin

Bacon

Panella

et al. 2004

Journal Cellular Physiology

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The impact of low-dose ultraviolet light (UV-light) on apoptotic susceptibility of keratinocytes (KCs) induced by TRAIL is unclear. Skin expresses a functional form of TRAIL, and while sun exposure influences TRAIL death receptors, a role for decoy receptors has not been evaluated. Unraveling mechanisms involving apoptotic sensitivity of KCs is important because skin is the first target of UV-light, and a site for commonly occurring cancers. Since apoptosis is a homeostatic process eliminating UV-light induced DNA damaged cells, elucidating molecular events regulating apoptosis enhances understanding of cutaneous photocarcinogenesis. Here we demonstrate low-dose UV-light enhances susceptibility of KCs to TRAIL-induced apoptosis. Low-dose UV-light selectively reduces decoy receptors, without influencing death receptor levels. UV-induced enhanced apoptotic susceptibility was reduced by over-expression of decoy receptor TRAIL-R4, but not TRAIL-R3; or treatment with thiol compound pyrrolidine dithiocarbamate (PDTC), which also enhanced TRAIL-R4 levels. Besides influencing decoy receptors, low-dose UV-light plus TRAIL also synergistically promoted cytochrome c and Smac release from mitochondria. Inhibitors directed against caspases 2, 3, 8, and 9 reduced the synergistic apoptotic response following low-dose UV-light plus TRAIL exposure; as did forced over-expression of Bcl-x and dominant negative (DN) constructs of FADD and caspase 9. Thus, relative levels of decoy receptors significantly influence susceptibility of KCs to TRAIL-induced apoptosis with concomitant low-dose UV-light exposure; in addition to the apoptotic pathway mediated by mitochondrial permeabilization.

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Loss of Fas-Ligand Expression in Mouse Keratinocytes during UV Carcinogenesis

Abstract: The incidence of skin cancer far exceeds the incidences of all other human cancers combined.

Cited by 78 publications

References 34 publications

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

Expression of CD95 (Fas) in sun‐exposed human skin and cutaneous carcinomas

Low‐dose UV‐radiation sensitizes keratinocytes to TRAIL‐induced apoptosis

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