Ultraviolet (UV) radiation present in sunlight is known to be responsible for the induction of most human skin cancers. Since cancers of the skin are the most prevalent form of human cancer, UV radiation is an important environmental carcinogen. The long-term objective of this proposal is to investigate the molecular mechanisms by which UV radiation induces skin cancer. Induction of tumors in rodents by defined chemicals has been shown to involve activation of specific oncogenes. However, it is not known whether UV radiation activates proto-oncogenes in a carcinogen-specific manner. Since the DNA damage induced by UV radiation is unique and differs from the lesions induced by any other carcinogen, it is quite possible that specific UV-induced alterations in oncogene structure can lead to the induction of tumors. Our previous studies have shown that human skin cancers occurring on sun-exposed body sites contain deletions, mutations, and amplifications in ras oncogenes. In this study, we plan to use UV-induced mouse tumors as a model system to determine whether they contain specific ras gene mutations, amplifications or deletions, and if so, whether they are similar to those found in human skin cancers occurring on sun-exposed body sites. Since the etiology of UV-induced murine skin cancers is more certain than that of human skin cancers, we can test the hypothesis that UV radiation activates particular oncogenes in a carcinogen-specific manner.
Our specific aims are: (1) To determine whether the UV-induced murine skin tumors contain specific mutations in ras oncogenes. (2) To determine whether the UV-induced murine skin cancers express amplified oncogenes. (3) To determine whether the UV-induced murine skin cancers display loss or rearrangement of oncogenes or the p53 tumor suppressor gene. Ras gene mutations will be analyzed by polymerase chain reaction followed by dot-blot hybridization to synthetic oligodeoxynucleotide probes designed to detect single base pair mutations. Amplification of selected oncogenes such as ras, myc, myb, fos, erbA, and erbB will be analyzed by Southern and Northern blot hybridization. Loss or rearrangement of selected oncogenes (ras, myc, myb, fos, erbA, and erbB) and the p53 gene will be analyzed by restriction fragment length polymorphism. In addition, UV-induced murine skin cancers will be analyzed for possible mutations in the p53 gene, because it is known that in some cancers, one of the p53 allele is lost, while the other is mutated. Information obtained from these studies may help to understand the molecular mechanisms of UV carcinogenesis.
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| 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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