Loss of fas-ligand expression in mouse keratinocytes during UV carcinogenesis

A. Ouhtit, A. Gorny, H. K. Muller, L. L. Hill, L. Owen-Schaub, H. N. Ananthaswamy

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Skin cells containing excessive ultraviolet (UV) radiation-induced DNA damage are eliminated by apoptosis that involves the p53 pathway and Fas/Fas-Ligand (Fas-L) interactions. To determine whether dysregulation of apoptosis plays a role in skin cancer development through disruption of Fas/Fas-L interactions, hairless SKH-hr1 mice were exposed to chronic UV irradiation from Kodacel-filtered FS40 lamps for 30 weeks. Their skin was analyzed for the presence of sunburn cells (apoptotic keratinocytes) and for Fas and Fas-L expression at various time points. A dramatic decrease in the numbers of morphologically identified sunburn cells and TUNEL-positive cells was detected as early as 1 week after chronic UV exposure began. After 4 weeks of chronic UV exposure, these cells were barely detectable. This defect in apoptosis was paralleled by an initial decrease in Fas-L expression during the first week of chronic UV irradiation and a complete loss of expression after 4 weeks. Fas expression, however, increased during the course of chronic UV exposure.p53 mutations were detected in the UV-irradiated epidermis as early as 1 week after irradiation began and continued to accumulate with further UV exposure. Mice exposed to chronic UV began to develop skin tumors after approximately 8 weeks, and all mice had multiple skin tumors by 24 weeks. Most of the tumors expressed Fas but not Fas-L. We conclude that chronic UV exposure may induce a loss of Fas-L expression and a gain in p53 mutations, leading to dysregulation of apoptosis, expansion of mutated keratinocytes, and initiation of skin cancer.

Original languageEnglish
Pages (from-to)1975-1981
Number of pages7
JournalAmerican Journal of Pathology
Issue number6
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Ouhtit, A., Gorny, A., Muller, H. K., Hill, L. L., Owen-Schaub, L., & Ananthaswamy, H. N. (2000). Loss of fas-ligand expression in mouse keratinocytes during UV carcinogenesis. American Journal of Pathology, 157(6), 1975-1981.