XPA gene-deficient, SCF-transgenic mice with epidermal melanin are resistant to UV-induced carcinogenesis.
Photobiologic investigations have been performed using animals without epidermal melanocytes. We developed xeroderma pigmentosum group A gene-deficient (XPA (-/-)), stem cell factor transgenic (SCF-Tg) mice, which one defective in nucleotide excision repair and have epidermal melanocytes, and investigated protective effects of epidermal melanin against UV-induced injuries. When irradiated to UVB, XPA (-/-) mice developed greatly enhanced responses including acute inflammation, cyclobutane pyrimidine dimer (CPD) formation, keratinocyte apoptosis, depletion of Langerhans cells and immunosuppression of contact hypersensitivity, but XPA (-/-), SCF-Tg mice showed much less responses to the same dose of UVB. XPA (-/-), SCF-Tg mice did not develop skin cancers after repeated exposures to UVB for 30 wk at a total dose of 72 J per cm(2), which induced a significant number of tumors even in wild-type, XPA (+/+) mice, and was lethal dose for XPA (-/-) mice. Dimethylbenz (alpha) anthracence (DMBA) induces DNA damages, which require XPA protein to be repaired. Topical application of DMBA produced a significant inflammation, CPD formation, apoptosis, immunosuppression, and skin cancers in XPA (-/-), SCF-Tg mice as well as XPA (-/-) mice. These findings indicate that epidermal melanin has a high ability to protect DNA damage by UVB radiation, and thereby, prevent UV-induced inflammation, immunosuppression, and carcinogenesis.
Yamazaki
Fumikazu
F
Department of Dermatology, Kansai Medical University, Moriguchi, Osaka, Japan. yamazakf@takii.kmu.ac.jp
Okamoto
Hiroyuki
H
Miyauchi-Hashimoto
Hiroko
H
Matsumura
Yasuhiro
Y
Itoh
Taketo
T
Tanaka
Kiyoji
K
Kunisada
Takahiro
T
Horio
Takeshi
T
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D003872:Dermatitis / Q000473:pathology / Q000503:physiopathology; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D007113:Immunity, Innate; D020287:In Situ Nick-End Labeling; D007801:Langerhans Cells / Q000473:pathology; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011740:Pyrimidine Dimers / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D019089:Stem Cell Factor / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum / Q000235:genetics; D051760:Xeroderma Pigmentosum Group A Protein
D002273:Carcinogens; D004268:DNA-Binding Proteins; D008543:Melanins; D011740:Pyrimidine Dimers; D019089:Stem Cell Factor; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene