P38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis

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

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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.

Original languageEnglish (US)
Pages (from-to)469-478
Number of pages10
JournalMolecular Carcinogenesis
Volume50
Issue number6
DOIs
StatePublished - Jun 2011

Fingerprint

p38 Mitogen-Activated Protein Kinases
Cyclooxygenase 2
Carcinogenesis
Transcription Factor AP-1
Skin
Keratinocytes
Transgenic Mice
Hairless Mouse
Skin Neoplasms
Solar System
Growth
Transgenes
Epidermis
Transcriptional Activation
Neoplasms
Transcription Factors
Pharmacology
Apoptosis
Staining and Labeling

Keywords

  • AP-1
  • COX-2
  • Dominant negative p38
  • Nonmelanoma skin cancer
  • Ultraviolet light

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Dickinson, S. E., Olson, E. R., Zhang, J., Cooper, S. J., Melton, T., Criswell, P. J., ... Bowden, G. T. (2011). P38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis. Molecular Carcinogenesis, 50(6), 469-478. https://doi.org/10.1002/mc.20734

P38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis. / 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.

In: Molecular Carcinogenesis, Vol. 50, No. 6, 06.2011, p. 469-478.

Research output: Contribution to journalArticle

Dickinson, SE, Olson, ER, Zhang, J, Cooper, SJ, Melton, T, Criswell, PJ, Casanova, A, Dong, Z, Hu, C, Saboda, K, Jacobs, ET, Alberts, DS & Bowden, GT 2011, 'P38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis', Molecular Carcinogenesis, vol. 50, no. 6, pp. 469-478. https://doi.org/10.1002/mc.20734
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. / P38 MAP kinase plays a functional role in UVB-Induced mouse skin carcinogenesis. In: Molecular Carcinogenesis. 2011 ; Vol. 50, No. 6. pp. 469-478.
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