Publication Date
2020
Document Type
Thesis
Committee Members
Michael G. Kemp, Ph.D. (Advisor); Jeffrey B. Travers , M.D., Ph.D. (Committee Member); Young-jie Xu, M.D., Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Skin cancer is the most prevalent human malignancy and is primarily caused by ultraviolet (UV) wavelengths of sunlight. However, the fact that most skin cancers occur in people over the age of 60 indicates that advantaged age is a second skin cancer risk factor. Why geriatric skin is prone to developing skin cancers is not clear, but several studies have shown that dermal fibroblasts in geriatric skin express lower levels of the hormone insulin-like growth factor-1 (IGF-1) than young adult skin and that deficient IGF-1 signaling negatively impacts how epidermal keratinocytes respond to UVB radiation. A major regulator of the cellular response to UVB-induced DNA damage response is the tumor suppressor protein p53, and a previous study indicated that p53 is not properly activated in UVB-irradiated human keratinocytes deficient in IGF-1 signaling. Using cultured human keratinocytes in vitro, we show here that several downstream transcriptional targets of p53, including the cell cycle-dependent kinase inhibitor p21, the translesion synthesis polymerase pol eta, and the DNA repair factors XPC and DDB, are not properly induced following UVB exposure in cells deprived of IGF-1. Using discarded human skin from routine panniculectomies, we show that the topical application of an IGF-1 receptor antagonist similarly abrogates the ability of UVB exposure to properly induce pol eta and p21. Because these various p53 target gene products are involved in delaying entry into S phase, accurately replicating UVB photoproducts, and removing UVB photoproducts from genomic DNA, our findings indicate that the inability of IGF-1-deficient geriatric skin properly activate p53-response genes may predispose geriatric skin to mutagenesis and carcinogenesis.
Page Count
123
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2020
Copyright
Copyright 2020, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0003-1594-7224
