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Carcinogenesis Advance Access originally published online on August 25, 2005
Carcinogenesis 2006 27(2):225-231; doi:10.1093/carcin/bgi220
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Carcinogenesis vol.27 no.2 © Oxford University Press 2005; all rights reserved.

Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor

Taghrid B. El-Abaseri, Sumanth Putta and Laura A. Hansen *

Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA

* To whom correspondence should be addressed at: Department of Biomedical Sciences, Creighton University School of Medicine, 723 N. 18th Street Criss II/Room 431, Omaha, NE 68178, USA. Tel: +1 402 280 4085; Fax: +1 402 280 2690; Email: lhansen{at}creighton.edu

Chronic exposure to ultraviolet (UV) irradiation induces skin cancer, in part, through epigenetic mechanisms that result in the deregulation of cell proliferation. UV irradiation also rapidly activates the epidermal growth factor receptor (EGFR). Since EGFR activation is strongly mitogenic in many cell types including keratinocytes of the skin, we hypothesized that UV-induced cutaneous proliferation results from EGFR activation. The role of EGFR activation in the response of the skin to UV was determined using Egfr-null and Egfr-wild-type skin grafted onto athymic nude mouse hosts, because Egfr-null mice survive only a few days after birth. EGFR was rapidly activated in mouse epidermis following exposure to UV, as detected by the phosphorylation of EGFR on tyrosine residues 992, 1045, 1068 and 1173. UV induced epidermal hyperplasia in Egfr-wild-type skin between 48 and 72 h post-UV. However, no epidermal hyperplasia occurred in Egfr-null skin. Baseline cell proliferation was similar in skin grafts of both genotypes. However, UV exposure increased cell proliferation, as measured by Ki67 immunohistochemistry and proliferating cell nuclear antigen immunoblotting, maximally at 48 h to a level more than three times higher in wild-type compared with Egfr-null skin. Apoptotic cell death, as measured by terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) analysis, was also increased in UV-exposed Egfr-null skin when compared with wild-type 1–2 days post-UV. These changes in cellular homeostasis after UV were accompanied by increased cyclin D expression in wild-type but not Egfr-null skin and increased expression of p53 and the cyclin-dependent kinase (CDK) inhibitor p21waf1 in Egfr-null skin when compared with wild-type. Collectively, these results demonstrate that the UV-induced activation of EGFR augments keratinocyte proliferation and suppresses apoptosis, leading to epidermal hyperplasia, associated with increased G1 cyclin expression and suppression of CDK inhibitor expression.


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