p38 Mitogen-Activated Protein Kinase Is Essential for Skin Tumor Development in Mice

¹Division of Dermatology and ²Renal Division, Department of Medicine, and ³Departments of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri; ⁴Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; and ⁵MRC Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom

^* To whom correspondence should be addressed. E-mail: tefimova{at}im.wustl.edu.

	Abstract

Activating Ras mutations occur in a large portion of human tumors. Yet, the signaling pathways involved in Ras-induced tumor formation remain incompletely understood. The mitogen-activated protein kinase pathways are among the best studied Ras effector pathways. The p38 mitogen-activated protein kinase isoforms are important regulators of key biological processes including cell proliferation, differentiation, survival, inflammation, senescence, and tumorigenesis. However, the specific in vivo contribution of individual p38 isoforms to skin tumor development has not been elucidated. Recent studies have shown that p38, a p38 family member, functions as an important regulator of epidermal keratinocyte differentiation and survival. In the present study, we have assessed the effect of p38 deficiency on skin tumor development in vivo by subjecting p38 knockout mice to a two-stage 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate chemical skin carcinogenesis protocol. We report that mice lacking p38 gene exhibited a marked resistance to development of 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin papillomas, with increased latency and greatly reduced incidence, multiplicity, and size of tumors compared with wild-type mice. Our data suggest that the underlying mechanism for reduced susceptibility to skin carcinogenesis in p38-null mice involves a defect in proliferative response associated with aberrant signaling through the two major transformation-promoting pathways: extracellular signal-regulated kinase 1/2-activator protein 1 and signal transducer and activator of transcription 3. These findings strongly suggest an in vivo role for p38 in promoting cell proliferation and tumor development in epidermis and may have therapeutic implication for skin cancer. [Cancer Res 2009;69(11):4648–55]

Key Words: p38d, skin carcinogenesis, epidermis, knockout mice, protein kinase