Date of Award

8-2006

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Edward J. Michaud

Committee Members

Cymbeline T. Culiat, Mitchel J. Doktycz, Mary Ann Handel, Jay R. Snoddy

Abstract

The mouse agouti protein is transiently expressed in the skin and signals through the melanocortin 1 receptor to switch pigment production of hair-follicle melanocytes from black to yellow. Ubiquitous over-expression of agouti protein in mice carrying the spontaneous dominant mutations Ay and Avy causes a pleiotropic syndrome characterized by solid yellow hair color, obesity, diabetes, and increased susceptibility to carcinogenesis in a wide variety of tissues, including the skin. Over-expression of agouti in the skin of keratin 14 (K14)- Agouti transgenic mice promotes skin carcinogenesis, even in the absence of obesity and diabetes. In this study cDNA microarray and qRT-PCR analyses are used to identify molecular changes in the skin of K14-Agouti mice associated with the promotion stage of carcinogenesis. Histological analysis of the skin revealed that there were no differences in gross morphology or in timing of hair- follicle stages between transgenic and control mice. However, cDNA microarray analysis identified 181 genes with significantly altered expression levels in the skin of transgenic mice. Additionally, qRT-PCR analysis demonstrated that the levels and temporal patterns of expression of 10 genes previously associated with skin and/or other epithelial cancers were significantly altered in the skin of K14- Agouti transgenic mice. Agouti-induced over-expression of these proto- oncogenes in the skin of K14-Agouti mice is proposed to be associated with the increased susceptibility to skin carcinogenesis. A hypothetical model is presented to explain the mechanism of action of the agouti protein as a tumor promoter in skin carcinogenesis. Additionally, strategies for future follow-on experiments to further investigate the role of agouti in tumor promotion and to test aspects of the proposed hypothetical model are discussed.

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