Carcinogenesis Advance Access published online on May 10, 2007
Carcinogenesis, doi:10.1093/carcin/bgm112
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Epidermal hyperplasia and papillomatosis in mice with a keratinocyte-restricted deletion of csk
1 Department of Biomedical Engineering and Orthopaedic Research Center, The Cleveland Clinic, Cleveland, OH, USA
2 Novartis Research Foundation, San Diego, CA, USA
3 Epithelial Damage, Repair and Tissue Engineering Project, CIEMAT, Madrid, Spain
4 Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY, USA
5 Department of Animal Science, Faculty of Agriculture, Kobe University, Kobe, Japan
Correspondence to: Takao Sakai, M.D., Ph.D., Department of Biomedical Engineering and Orthopaedic Research Center/ND20, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. TEL: 216-445-3223; FAX: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 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.
Key Words: Csk • Src-family tyrosine kinases • keratinocytes • epidermal hyperplasia and papillomatosis • stem cells
* These authors have contributed equally to this work
Received January 10, 2007; revised April 26, 2007; accepted April 30, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Serrels, A. Serrels, S. M. Mason, C. Baldeschi, G. H. Ashton, M Canel, L. J. Mackintosh, B. Doyle, T. P. Green, M. C. Frame, et al. A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model Carcinogenesis, February 1, 2009; 30(2): 249 - 257. [Abstract] [Full Text] [PDF]
|
|