p38 MAP kinase plays a functional role in UVB-induced mouse skin carcinogenesis.
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.
Department of Pharmacology, University of Arizona, Tucson, Arizona 85724, USA.
Sally E
SE
Dickinson
Erik R
ER
Olson
Jack
J
Zhang
Simon J
SJ
Cooper
Tania
T
Melton
P Jane
PJ
Criswell
Ana
A
Casanova
Zigang
Z
Dong
Chengcheng
C
Hu
Kathylynn
K
Saboda
Elizabeth T
ET
Jacobs
David S
DS
Alberts
G Tim
GT
Bowden
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000502:physiology; D018450:Disease Progression; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D008156:Luciferases; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases
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