The studies proposed in this grant application are focused on investigating the mechanisms involved in the resistance of CD1 knockout mice to UV carcinogenesis. The rationale for these studies is based on a novel and interesting observation that CD1 knockout mice are extremely resistant to UV carcinogenesis and phototoxicity, and their skin contains a high number of apoptotic keratinocytes compared to CD1+/+ mice. Our recent studies indicate that UV induces the expression of CD1 protein in wild-type mouse skin, suggesting that CD1 is a target for UV. Based on these results, we hypothesize that the resistance of CD1-/- mice to UV carcinogenesis may be associated with persistent elimination of UV damaged, potentially malignant keratinocytes. The following specific aims will be used to test this hypothesis: (1) Determine whether transfection of the CD1 gene into CD1-/- mouse keratinocytes restores resistance to UV-induced apoptosis and susceptibility to neoplastic transformation, (2) Determine whether the increased resistance of CD1-/- mice to UV carcinogenesis is due to persistent elimination of UV-damaged keratinocytes from the skin, and (3) Determine whether CD1-/-mouse skin is resistant to UV-induced p53 mutations compared to CD1+/+ mouse skin. To study Specific Aim 1, keratinocyte cultures from neonatal CD1-/- and +/+ will be established and tested for their susceptibility to UV-induced apoptosis, terminal differentiation, and neoplastic transformation. In addition, fibroblasts from CD1-/- and +/+ mice will be tested to determine if the defect is general or limited to keratinocytes. More importantly, CD1 gene will be transfected into CD1-/- keratinocytes to investigate the role of CD1 in UV-induced apoptosis, terminal differentiation and neoplastic transformation. To study Specific Aims 2 and 3, CD1-/- and +/+ mice will be exposed to acute or chronic UV irradiation and their skin analyzed for (i) sunburn and TUNEL-positive cells, (ii) expression of cell cycle and apoptosis-associated proteins such as p53, p21 Waf1/Cip1, Fas, Fas-L, Bax, and Bcl-2, and (ii) kinetics (incidence, latency, and persistence) of induction of UV-specific p53 mutations by allele-specific polymerase chain reaction. Data generated from these studies should shed new light on the role of CD1 in photocarcinogenesis. This information is important for understanding the interactions between UV, the CD1 gene, and skin cancer. Although the important role of CD1 molecule in antigen presentation and immune regulation is well known, virtually nothing is known in regard to its role in skin cancer development. Our preliminary findings, resistance to UV carcinogenesis and increased apoptosis in CD1-/- mice, suggest a role for CD1 in cell cycle regulation. Because UV causes immunosuppression and induces skin cancer, and CD1 protein plays a role in antigen presentation and immune regulation, understanding the mechanisms involved in the resistance of CD1-/- mice to UV carcinogenesis may also contribute to the understanding of the relationship between UV carcinogenesis and UV-induced immunosuppression. In addition, the results may suggest that similar mechanisms be involved in skin cancer development in humans.
| Benjamin, Cara L; Melnikova, Vladislava O; Ananthaswamy, Honnavara N (2008) P53 protein and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol 624:265-82 |
| Benjamin, Cara L; Ullrich, Stephen E; Kripke, Margaret L et al. (2008) p53 tumor suppressor gene: a critical molecular target for UV induction and prevention of skin cancer. Photochem Photobiol 84:55-62 |
| Benjamin, Cara L; Ananthaswamy, Honnavara N (2008) Oncogenic potential of BRAF versus RAS. Cancer Lett 261:137-46 |
| Pacifico, A; Goldberg, L H; Peris, K et al. (2008) Loss of CDKN2A and p14ARF expression occurs frequently in human nonmelanoma skin cancers. Br J Dermatol 158:291-7 |
| Benjamin, Cara L; Ananthaswamy, Honnavara N (2007) p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol 224:241-8 |
| Benjamin, Cara L; Melnikova, Vladislava O; Ananthaswamy, Honnavara N (2007) Models and mechanisms in malignant melanoma. Mol Carcinog 46:671-8 |
| Kim, Seungwon; Yazici, Yasemin D; Calzada, Gabriel et al. (2007) Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther 6:1785-92 |
| Huang, Chun-Ming; Ananthaswamy, Honnavara N; Barnes, Stephen et al. (2006) Mass spectrometric proteomics profiles of in vivo tumor secretomes: capillary ultrafiltration sampling of regressive tumor masses. Proteomics 6:6107-16 |
| Wolf, Peter; Nghiem, Dat X; Walterscheid, Jeffrey P et al. (2006) Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis. Am J Pathol 169:795-805 |
| Melnikova, Vladislava O; Ananthaswamy, Honnavara N (2005) Cellular and molecular events leading to the development of skin cancer. Mutat Res 571:91-106 |
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