Identification of a non-dividing subpopulation of mouse and human epidermal cells exhibiting high levels of persistent ultraviolet photodamage.

The distribution and persistence of cyclobutane pyrimidine dimers were investigated in mouse skin after chronic and acute exposures to ultraviolet-B radiation. We found that DNA damage accumulated in response to chronic irradiation and persisted in a unique set of epidermal cells located at the basal layer. Treatment with a tumor promoter caused the heavily damaged epidermal cells to divide and p53-immunopositive clusters to form within 24 h suggesting that these cells may be progenitors of the mutant p53 clusters associated with actinic keratoses and squamous cell carcinomas. In contrast to low fluence chronic irradiation, daily treatment with a higher fluence of ultraviolet-B produced extensive hyperplasia and considerably reduced penetration of photodamage. Exposure of chronically irradiated skin to an acute "sunburn dose" of ultraviolet-B also produced significant epidermal hyperplasia and resulted in complete loss of heavily damaged basal cells within 4 d postirradiation. The occurrence and distribution of cyclobutane dimers in human skin correlated well with putative sunlight exposure and resembled that observed in ultraviolet-B-irradiated mice. Heavily damaged basal cells were observed at various sites, including those receiving sporadic sunlight exposure, suggesting that these cells may play an important role in carcinoma formation in humans.

[1]  W. Pierceall,et al.  MOLECULAR MECHANISMS OF ULTRAVIOLET RADIATION CARCINOGENESIS , 1990, Photochemistry and photobiology.

[2]  F. Gruijl,et al.  Early p53 alterations in mouse skin carcinogenesis by UVB radiation: immunohistochemical detection of mutant p53 protein in clusters of preneoplastic epidermal cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Simon,et al.  A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Moan,et al.  Environmental UV Photobiology , 1993, Springer US.

[5]  M A Weinstock,et al.  Nonmelanoma skin cancer in the United States: incidence. , 1994, Journal of the American Academy of Dermatology.

[6]  F. Gruijl,et al.  Influence of Ozone Depletion on the Incidence of Skin Cancer Quantitative Prediction , 1993 .

[7]  A. Ziegler,et al.  Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Gina A. Taylor,et al.  Involvement of Follicular Stem Cells in Forming Not Only the Follicle but Also the Epidermis , 2000, Cell.

[9]  T. Fears,et al.  Incidence of Nonmelanoma Skin Cancer in the United States. , 1984 .

[10]  S. Shimizu,et al.  Quantitative Detection of Ultraviolet Light‐induced Photoproducts in Mouse Skin by Immunohistochemistry , 1995, Japanese journal of cancer research : Gann.

[11]  J. Trosko,et al.  Excision of pyrimidine dimers from epidermal DNA and nonsemiconservative epidermal DNA synthesis following ultraviolet irradiation of mouse skin. , 1975, Cancer research.

[12]  T. Slaga,et al.  Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. , 1986, Cancer research.

[13]  D. Mitchell,et al.  Attenuation of DNA Damage in the Dermis and Epidermis of the Albino Hairless Mouse by Chronic Exposure to Ultraviolet-A and -B Radiation¶ , 2001, Photochemistry and photobiology.

[14]  D. Mitchell,et al.  Effects of chronic low-dose ultraviolet B radiation on DNA damage and repair in mouse skin. , 1999, Cancer research.

[15]  D. Grube,et al.  Induction and persistence of pyrimidine dimers in the epidermal DNA of two strains of hairless mice. , 1977, Cancer research.

[16]  L. Mullenders,et al.  Ultraviolet-induced cyclobutane pyrimidine dimers are selectively removed from transcriptionally active genes in the epidermis of the hairless mouse. , 1993, Cancer research.

[17]  R. Morris,et al.  Evidence that cutaneous carcinogen-initiated epithelial cells from mice are quiescent rather than actively cycling. , 1997, Cancer research.

[18]  R. Baan,et al.  Induction, repair and accumulation of thymine dimers in the skin of UV-B-irradiated hairless mice. , 1991, Carcinogenesis.

[19]  R. Baan,et al.  Detection of thymine dimers in suprabasal and basal cells of chronically UV-B exposed hairless mice. , 1993, The Journal of investigative dermatology.

[20]  F. Gruijl,et al.  In Situ Molecular Dosimetry and Tumor Risk: UV‐lnduced DNA Damage and Tumor Latency Time‡ , 1998, Photochemistry and photobiology.

[21]  M. Skolnick,et al.  Genetic predisposition to melanoma. , 1994, European journal of cancer.

[22]  Johnson Be.  Formation of thymine containing dimers in skin exposed to ultraviolet radiation. , 1978 .

[23]  F. Urbach,et al.  Ultraviolet radiation and skin cancer of humans. , 1997, Journal of photochemistry and photobiology. B, Biology.

[24]  B. Johnson,et al.  Dose response, wavelength dependence and rate of excision of ultraviolet radiation-induced pyrimidine dimers in mouse skin DNA. , 1978, Biochimica et biophysica acta.

[25]  R. Tarone,et al.  Frequent clones of p53-mutated keratinocytes in normal human skin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.