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.

Protection against UVR Involves MC1R-Mediated Non-Pigmentary and Pigmentary Mechanisms In Vivo

“…The evidence from studies on human skin and pigmented mouse models indicates that epidermal melanin protects against UVR (Yamazaki et al, 2004;Yamaguchi et al, 2006;Kato et al, 2007). However, it is important to understand how MC1R photoprotects, and the role of melanin type in relation to the detrimental effects of UVR to make balanced decisions about UVR exposure in terms of DNA damage and potential benefits from cutaneous vitamin D synthesis (Moan et al, 2008).…”

Loss of Xeroderma Pigmentosum C (Xpc) Enhances Melanoma Photocarcinogenesis in Ink4a-Arf–Deficient Mice

“…Thus, the mitogenic stimulus conferred by ectopic and broad expression of Tg(MT-HGF/SF) seems to define melanocyte localization and, as a consequence, may dictate the histology of melanoma. Similarly, in Xpa À/À Tg(Scf) mice, Yamazaki et al (26) also reported melanocyte retention in the epidermis comparable to human skin; upon high-dose UVB irradiation (150 J/cm 2 over 10 weeks), the transgenic mice also developed melanomas with features suggestive of humanized architecture (i.e., lentigo maligna melanoma and nodular melanomas). Because the genetic bases of melanomas from these models have not been fully clarified, the molecular correlates of these histologic features are not known.…”

Effect of Halophilic Bacterium, Haloarcula vallismortis, Extract on UV-induced Skin Change

“…이 중 UVB는 피부 광노화의 대표적인 원인으로 피부에서 염증반응을 일으키며, 축 적된 UV자극은 피부 당화(glycation)산물을 조직에 축 적시켜 장벽손상 및 노화를 촉진시킨다 [1]. 또 표피 기 저층과 진피 상부까지 도달하여 피부각화를 지속시키 고 각질세포 및 섬유아세포의 DNA pyrimidine 잔기에 손상을 주어 cyclobutane pyrimidine dimer (CPD)를 형 성한다 [2]. 형성된 CPD는 피부에서 여러 중요한 반응 을 일으키는데 각종 염증반응을 유도하고 면역억제반 응을 일으켜 보호장벽으로서의 기능을 약화시킨다 [3].…”