Carcinogenesis Advance Access originally published online on May 10, 2007
Carcinogenesis 2007 28(10):2074-2081; doi:10.1093/carcin/bgm112
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Epidermal hyperplasia and papillomatosis in mice with a keratinocyte-restricted deletion of csk
1 Department of Biomedical Engineering and Orthopaedic Research Center/ND20, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
2 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121 USA
3 Epithelial Damage, Repair and Tissue Engineering Project, CIEMAT, Madrid, 28040, Spain
4 Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021, USA
5 Department of Animal Science, Faculty of Agriculture, Kobe University, Kobe 657-8501, Japan
* To whom correspondence should be addressed. Tel: +1 216 445 3223; Fax: +1 216 444 9198; Email: sakait{at}ccf.org
The Src family kinases (SFKs) are believed to play critical roles in malignant transformation, as well as in growth, invasion and dissemination of neoplastic tissue. Inhibition of SFK-mediated signal transduction and activation of downstream targets inhibits tumor progression. To determine whether constitutive activity of SFK per se is sufficient to induce tumorigenesis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of the SFK-negative regulator csk (Csk-K5 mice). Even though expression levels of SFKs were lower in C-terminal Src kinase (Csk)-null keratinocytes, activity levels were higher than in control keratinocytes. At the age of 3 months, all Csk-K5 mice displayed signs of chronic inflammation in dermis and epidermal hyperplasia. About 19% of Csk-K5 mice (7 out of 36) developed papillomatous lesions. However, these lesions did not show any signs of neoplastic transformation over the next 8 months. Epidermal hyperplasia and hyperkeratosis in Csk-K5 mice were associated with an increased number of stem cells in the interfollicular epidermis, an increased proliferation of basal keratinocytes and a delayed terminal differentiation of the suprabasal keratinocytes. Our results clearly demonstrate that even though SFK-mediated signaling promotes tumor progression, elevated activity of SFKs in vivo alone is not sufficient to induce neoplastic transformation.
Abbreviations: Csk, C-terminal Src kinase; DEJ, dermal–epidermal junction; FAK, focal adhesion kinase; mAb, monoclonal antibody; MEM, modified Eagle’s medium; PBS, phosphate-buffered saline; SFK, Src family kinase
These authors contributed equally to this work. Received January 10, 2007; revised April 26, 2007; accepted April 30, 2007.
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