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

Abstract

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.

• Authors: Sally E Dickinson, Erik R Olson, Jack Zhang, Simon J Cooper, Tania Melton, P Jane Criswell, Ana Casanova, Zigang Dong, Chengcheng Hu, Kathylynn Saboda, Elizabeth T Jacobs, David S Alberts, G Tim Bowden
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 50 Issue 6 Pg. 469-78 (Jun 2011) ISSN: 1098-2744 [Electronic] United States
• PMID: 21268131 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley-Liss, Inc.

Chemical References

• Luciferases
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (radiation effects)
• Blotting, Western
• Cell Proliferation (radiation effects)
• Cyclooxygenase 2 (physiology)
• Disease Progression
• Epidermis (metabolism, pathology, radiation effects)
• Female
• Genes, Dominant
• Humans
• Immunoenzyme Techniques
• Luciferases (metabolism)
• Mice
• Mice, Hairless
• Mice, Transgenic
• Skin Neoplasms (etiology, metabolism, pathology)
• Ultraviolet Rays (adverse effects)
• p38 Mitogen-Activated Protein Kinases (physiology)