p38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis

• Published in: Molecular carcinogenesis 2011-06, Vol.50 (6), p.469-478
• Main Authors: Dickinson, Sally E., Olson, Erik R., Zhang, Jack, Cooper, Simon J., Melton, Tania, Criswell, P. Jane, Casanova, Ana, Dong, Zigang, Hu, Chengcheng, Saboda, Kathylynn, Jacobs, Elizabeth T., Alberts, David S., Bowden, G. Tim
• Format: Article
• Language: English
• Subjects: Animals; AP-1; Apoptosis - radiation effects; Blotting, Western; Cell Proliferation - radiation effects; COX-2; Cyclooxygenase 2 - physiology; Disease Progression; dominant negative p38; Epidermis - metabolism; Epidermis - pathology; Epidermis - radiation effects; Female; Genes, Dominant; Humans; Immunoenzyme Techniques; Luciferases - metabolism; Mice; Mice, Hairless; Mice, Transgenic; nonmelanoma skin cancer; p38 Mitogen-Activated Protein Kinases - physiology; Skin Neoplasms - etiology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; ultraviolet light; Ultraviolet Rays - adverse effects
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20734

UVB irradiation of epidermal keratinocytes results in the activation of the p38 mitogen‐activated protein kinase (MAPK) pathway and subsequently activator protein‐1 (AP‐1) transcription factor activation and cyclooxygenase‐2 (COX‐2) expression. AP‐1 and COX‐2 have been shown to play functional roles in UVB‐induced mouse skin carcinogenesis. In this study, the experimental approach was to express a dominant negative p38α MAPK (p38DN) in the epidermis of SKH‐1 hairless mice and assess UVB‐induced AP‐1 activation, COX‐2 expression, and the skin carcinogenesis response in these mice compared to wild‐type littermates. We observed a significant inhibition of UVB‐induced AP‐1 activation and COX‐2 expression in p38DN transgenic mice, leading to a significant reduction of UVB‐induced tumor number and growth compared to wild‐type littermates in a chronic UVB skin carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki‐67 staining in p38DN mice compared to wild‐type. Although we detected no difference in chronic apoptotic rates between transgenic and nontransgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB‐induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV‐induced skin cancer in patients with sun damaged skin, and suggest that inhibition of p38 signaling reduces skin carcinogenesis by inhibiting COX‐2 expression and proliferation of UVB‐irradiated cells. © 2011 Wiley‐Liss, Inc.