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

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 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.

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

“…Exposure to lower doses of UVB induces proliferation of the epidermal keratinocytes in the skin, leading to epidermal hyperplasia (28). We first established the role of FGF-2 in UVB-induced acute damage by exposing JB6 cells to sub-apoptotic dose of UVB (50 mj/cm 2 ).…”

Repression of SHP-1 expression by p53 leads to trkA tyrosine phosphorylation and suppression of breast cancer cell proliferation

“…p53 repression of SHP-1 induces trkA-dependent growth arrest X Montano therapeutic drugs can activate receptor tyrosine kinases (Benhar et al, 2002;El-Abaseri et al, 2006). Agents such as AraC induce trkA transcription or activation (Jagjit and Anthony, 1998; Xie et al,…”

“…Repression of SHP-1 expression by wtp53 leads to wt trkA-Y674/Y675 phosphorylation Chemotherapeutic drugs activate receptor tyrosine kinases through mechanisms such as oxidative stress or by activating protein kinases (Benhar et al, 2002;El-Abaseri et al, 2006). To test if ActD promotes trkA tyrosine phosphorylation, in the absence of p53, trkA was immunoprecipitated from NGF-stimulated or ActD-treated non-transfected or wt-trkA stably transfected p53À/À fibroblasts, and analysed by immunoblotting with 4G10 antibodies.…”

Avaliação da eficácia fotoprotetora, penetração cutânea e segurança de formulações cosméticas contendo extratos de chá verde e 'Ginkgo biloba'

“…PUTTA; HANSEN, 2006). Tem sido sugerido que os processos de apoptose e proliferação estão intimamente relacionados e que a exposição crônica à radiação UV pode desregular estes dois eventos, levando ao desenvolvimento de câncer de pele (MEGURO et al, 1999;OUHTIT et al, 2000;LU et al, 1999;HENESSY et al, 2005).…”

“…Vários estudos que avaliam substâncias ativas com finalidade fotoprotetora têm realizado a quantificação da hiperplasia da epiderme induzida pela radiação UV, por meio da medida da espessura da epiderme viável e da contagem de camadas de células nucleadas desta camada (LU et al, 1999;EL-ABASERI;PUTTA;HANSEN, 2006). Para a determinação do mecanismo de ação de diversas substâncias naturais e sintéticas na fotoproteção, vários estudos têm utilizado modelo animal, sendo que o camundongo sem pêlo tem se apresentado um modelo útil para tal finalidade, uma vez que mimetiza os efeitos da radiação UV na pele humana.…”