Resistance of CD1d-/- mice to ultraviolet-induced skin cancer is associated with increased apoptosis.
Inhibition of p53-induced epidermal apoptosis, generation of p53 mutations, and suppressor T cells are the critical events responsible for the induction and development of UV-induced skin cancers. Recently, we demonstrated that CD1d knockout mice were resistant to UV-induced immunosuppression, prompting us to further address the role of CD1d in regulating UV carcinogenesis. We, therefore, investigated the response of wild-type (WT) and CD1d-/- mice to UV carcinogenesis. We found that although 100% of WT mice developed skin tumors after 45 weeks of UV irradiation, only 60% of CD1d-/- mice developed skin tumors. Surprisingly, keratinocytes and fibroblasts from CD1d-/- mice were more sensitive to UV-induced apoptosis and persisted longer than cells derived from WT mice. In addition, epidermis and dermis taken from chronically UV-irradiated CD1d-/- mice harbored significantly fewer p53 mutations than WT mice. Our findings identify an unexpected and novel function for CD1d as a critical molecule regulating UV carcinogenesis, by inhibiting apoptosis to prevent elimination of potentially malignant keratinocytes and fibroblasts.
Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA.
Yasuhiro
Y
Matsumura
Angus M
AM
Moodycliffe
Dat X
DX
Nghiem
Stephen E
SE
Ullrich
Honnavara N
HN
Ananthaswamy
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000502:physiology*; D055610:Antigens, CD1d; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000528:radiation effects; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D011836:Radiation Tolerance; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D018949:Antigens, CD1; D055610:Antigens, CD1d; D016159:Tumor Suppressor Protein p53