This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by He, Y.-Y. Articles by Chignell, C. F. Search for Related Content PubMed PubMed Citation Articles by He, Y.-Y. Articles by Chignell, C. F.

UVA-Induced Cell Cycle Progression Is Mediated by a Disintegrin and Metalloprotease/Epidermal Growth Factor Receptor/AKT/Cyclin D1 Pathways in Keratinocytes

¹ Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina and ² Section of Dermatology, Department of Medicine, University of Chicago, Chicago, Illinois

Requests for reprints: Yu-Ying He, Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637. Phone: 773-795-4696; Fax: 773-702-8398; E-mail: yyhe{at}medicine.bsd.uchicago.edu.

Key Words: UVA • Cell cycle • ADAM • EGFR • AKT

UVA (315–400 nm), which constitutes 95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer. [Cancer Res 2008;68(10):3752–8]