Mechanisms of Epidermal Growth Factor Receptor Regulation of Epidermal Proliferation and Skin Tumorigenesis in Response to Ultraviolet Irradiation.
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Authors
El-Abaseri, Taghrid
Issue Date
2004-08
Volume
Issue
Type
Dissertation
Language
en_US
Keywords
Alternative Title
Abstract
The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, regulates both skin biology and carcinogenesis. We hypothesized that EGFR-dependent signal transduction increases normal keratinocyte proliferation and proliferation in response to ultraviolet (UV) irradiation, resulting in increased skin tumor growth. The mechanisms of EGFR’s mitogenic effects on keratinocytes were examined using EGFR null keratinocytes and an EGFR inhibitor. Genetic ablation or inhibition of EGFR decreased keratinocyte proliferation and resulted in epidermal hypoplasia. EGFR regulated keratinocyte progression through multiple cell cycle checkpoints. In vivo, EGFR controlled keratinocyte progression through the Gi to S-phase transition. In contrast, EGFR null keratinocytes accumulated in G2/M under standard culture conditions. However, the addition of TGF-a to the culture medium revealed a defect in Gi progression in EGFR null keratinocytes as well. Both EGFR null keratinocytes and inhibitor-treated epidermis expressed decreased levels of cyclin D and E and increased levels of cyclin A and B1. EGFR-dependent activation of extracellular-signal regulated kinases (ERK1/2), p38 kinase and c-Jun NH2-terminal kinase (JNK) increased keratinocyte proliferation.|Ultraviolet irradiation (UV), a common environmental carcinogen, causes both acute and long-lasting damage to the skin. We investigated the role of EGFR in regulating the UV response of the skin using EGFR null keratinocytes, skin grafting, and an EGFR inhibitor. Exposure to UV rapidly activated EGFR in the skin. This UV-induced activation of EGFR altered the response of the skin to UV. EGFR-dependent signaling increased keratinocyte proliferation, suppressed mitochondrial-mediated apoptosis, and accelerated epidermal hyperplasia in response to UV. Abrogation of EGFR blocked the UV-induced activation of mitogen activated protein kinases (MAPK) and phosphatidyl- inositol 3-kinase (PI3K)/AKT signaling pathways. Keratinocyte proliferation in response to UV was modulated by the EGFR-dependent activation of JNK MAP kinases and PI3K/AKT.|Based on the above findings, the importance of EGFR signaling in the growth of UV-induced skin tumors, the most common human malignancy, was established. Upon inhibition of the UV-induced activation of EGFR in genetically initiated v-rasHa transgenic Tg.AC mice, both tumor number and tumor volume were decreased by approximately 50%. Decreased tumorigenesis was due to the short-lived inhibition of the UV-induced EGFR activation, since proliferation, apoptosis and differentiation were not altered in the papillomas. Blocking this activation by UV, using an EGFR inhibitor, suppressed the UV-induced activation of MAP kinases and PI3K/AKT signaling. Inhibition or genetic ablation of EGFR reduced proliferation, enhanced apoptosis, and delayed epidermal hyperplasia following multiple UV exposures. Taken together, the data provide insight into the mechanisms by which EGFR enhances keratinocyte proliferation under normal growth conditions and during UV-induced skin tumorigenesis. EGFR’s regulation of the response of the skin to UV suggests that interruption of EGFR-dependent signaling prior to UV exposure may be an effective mean to prevent UV-induced skin tumorigenesis. Moreover, understanding these specific EGFR-dependent signaling pathways involved in the UV response should stimulate further research into the role of EGFR-dependent signaling pathways in other UV-induced skin pathology including inflammation and photoaging.
Description
Citation
Publisher
Creighton University
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Copyright is retained by the Author.
A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.