p38 MAP Kinase Plays a Functional Role in UVB-induced Mouse Skin Carcinogenesis

Mol Carcinog. 2011 Jun;50(6):469-78. doi: 10.1002/mc.20734. Epub 2011 Jan 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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