XPA gene-deficient, SCF-transgenic mice with epidermal melanin are resistant to UV-induced carcinogenesis.

Abstract

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.

• Authors: Fumikazu Yamazaki, Hiroyuki Okamoto, Hiroko Miyauchi-Hashimoto, Yasuhiro Matsumura, Taketo Itoh, Kiyoji Tanaka, Takahiro Kunisada, Takeshi Horio
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 123 Issue 1 Pg. 220-8 (Jul 2004) ISSN: 0022-202X [Print] United States
• PMID: 15191564 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• DNA-Binding Proteins
• Melanins
• Pyrimidine Dimers
• Stem Cell Factor
• Xeroderma Pigmentosum Group A Protein
• Xpa protein, mouse
• 9,10-Dimethyl-1,2-benzanthracene

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Carcinogens
• DNA Damage
• DNA-Binding Proteins (genetics)
• Dermatitis (pathology, physiopathology)
• Epidermis (pathology, radiation effects)
• Immunity, Innate
• In Situ Nick-End Labeling
• Langerhans Cells (pathology)
• Melanins (metabolism)
• Melanocytes (metabolism, pathology, radiation effects)
• Mice
• Mice, Hairless
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Pyrimidine Dimers (metabolism)
• Skin Neoplasms (chemically induced, pathology, physiopathology)
• Stem Cell Factor (genetics)
• Ultraviolet Rays (adverse effects)
• Xeroderma Pigmentosum (genetics)
• Xeroderma Pigmentosum Group A Protein