The objectives of this proposal are to determine the distinct roles that protein kinase C (PKC) isoforms (delta and epsilon) play in multistage (initiation, promotion and progression) mouse skin carcinogenesis. Knowledge obtained will contribute to the management of human squamous cell carcinoma (SCC), a predominant nonmelanoma metastatic human skin cancer. PKC, a phospholipid-dependent protein kinase, is a major intracellular receptor for the tumor promoter phorbol ester TPA. PKC represents a family of eleven isozymes (alpha, betaI, betaII, gamma, delta, epsilon, sigma, eta, theta, lambda, and mu), and six of these PKC isoforms (alpha, delta, epsilon, eta, sigma and mu) are expressed in mouse epidermis. To determine the in vivo functional specificity of PKC isoforms in mouse skin carcinogenesis, we have generated transgenic FVB/N mouse lines that overexpress epitope tagged PKCalpha, PKCdelta or PKCepsilon isozyme in epidermis under the control of the human keratin 14 promoter. Since PKC is the key receptor for TPA, the DMBA-TPA protocol was used to induce skin tumors to investigate PKC isoform specificity in these transgenic mice. We found that PKCalpha overexpression had no effect on skin tumor promotion by TPA, PKCS overexpression suppressed the formation of both papilloma and SCC while PKCE overexpression induced metastatic SCC formation independently of prior papilloma development. Based on these observations, we plan to test two hypotheses: 1) PKCdelta and PKCepsilon expression levels determine skin tumor formation susceptibility as the result of modulation of specific steps of mouse skin carcinogenesis (e.g., initiation, promotion and/or progression). 2) Skin tumor suppression in PKCdelta transgenic mice and development of metastatic SCC in PKCepsilon transgenic mice are associated with the altered expression of specific genes and proteins leading to an imbalance within normal cell proliferation, differentiation and apoptosis. We propose the following specific aims to test the hypotheses:
Specific Aim #1. To determine, using several mouse models (transgenic and knockout), whether PKCdelta or PKCepsilon expression level determines susceptibility to skin tumor formation.
Specific Aim #2. To determine, using PKC-inducible transgenic mice, whether tumor suppression in PKCdelta and carcinoma development in PKCepsilon transgenic mice are the results of the effects of transgene overexpression on the initiation, promotion and/or progression stage of carcinogenesis.
Specific Aim #3. To find clues about the mechanisms associated with the opposing effects of PKCdelta and PKCepsilon, on mouse skin carcinogenesis by analysis of gene expression using the cDNA expression array.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemical Pathology Study Section (CPA)
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Johnson, Ronald L
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Hafeez, Bilal Bin; Meske, Louise; Singh, Ashok et al. (2016) Tissue-specific conditional PKC? knockout mice: a model to precisely reveal PKC? functional role in initiation, promotion and progression of cancer. Oncotarget 7:33069-80
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Sand, Jordan Marshall; Bin Hafeez, Bilal; Aziz, Moammir Hasan et al. (2012) Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase Cýý with Stat3 involve integration with ERK1/2. Mol Carcinog 51:291-302
Hafeez, Bilal Bin; Zhong, Weixiong; Weichert, Jamey et al. (2011) Genetic ablation of PKC epsilon inhibits prostate cancer development and metastasis in transgenic mouse model of prostate adenocarcinoma. Cancer Res 71:2318-27
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Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E et al. (2010) PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas. J Invest Dermatol 130:270-7
Aziz, Moammir Hasan; Sundling, Kaitlin Elizabeth; Dreckschmidt, Nancy Ellen et al. (2009) Protein kinase Cepsilon inhibits UVR-induced expression of FADD, an adaptor protein, linked to both Fas- and TNFR1-mediated apoptosis. J Invest Dermatol 129:2011-21
Aziz, Moammir H; Dreckschmidt, Nancy E; Verma, Ajit K (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res 68:9024-32

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