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Carcinogenesis Advance Access published online on August 25, 2005
Carcinogenesis, doi:10.1093/carcin/bgi220
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received June 6, 2005
Revised July 29, 2005
Accepted August 19, 2005

CANCER BIOLOGY

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

Taghrid B. El-Abaseri 1, Sumanth Putta 1, and Laura A. Hansen 1*

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

* To whom correspondence should be addressed.
Laura A. Hansen, E-mail: lhansen{at}creighton.edu


  Abstract

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 wild type skin grafted onto athymic nude mouse hosts, because Egfr null mice survive for 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 PCNA immunoblotting, maximally at 48 h to a level more than three times higher in wild type compared to Egfr null skin. Apoptotic cell death, as measured by TUNEL analysis, was also increased in UV-exposed Egfr null skin when compared to wild type 1-2 d 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 to 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.

Keywords: epidermal growth factor receptor; proliferation; p21; ultraviolet light; apoptosis.
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