| | Down-regulation of the tumor suppressor gene C-terminal Src kinase: An early event during premalignant colonic epithelial hyperproliferation☆Edited by Beat Imhof Received 11 March 2005; received in revised form 3 May 2005; accepted 6 May 2005. published online 03 June 2005. Abstract Hyperproliferation of the premalignant epithelium is critical for colonic carcinogenesis; however the mechanisms remain largely unexplored. We report herein that prior to occurrence of neoplastic lesions in the azoxymethane-rat model of colon carcinogenesis; the tumor suppressor gene C-terminal Src kinase (Csk) was down-regulated with a concomitant increase in Src activity. Furthermore, pharmacological or genetic (RNA interference) inhibition of Csk resulted in increased proliferation in colon cancer cell lines through the mitogen-activated protein kinase dependent pathway. Thus, we demonstrate, for the first time, that Csk suppression is an important early event in colorectal cancer pathogenesis. Abbreviations: CRC, colorectal cancer, Csk, C-terminal Src kinase, AOM, azoxymethane, BrDu, 5′bromo 2′deoxyuridine, MAP kinase, mitogen-activated protein kinase, MEK, MAP kinase kinase, PCNA, proliferating cell nuclear antigen, shRNA, short hairpin-loop RNA a Department of Internal Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA b Department of Pathology, University of Chicago Hospitals and Clinics, Chicago, IL, USA c HTS Laboratory, ASINEX, 5 Gabrichevskogo St. Bldg 8, Moscow 123367, Russia  Corresponding author. Fax: +1 847 733 5451/570 8011.
☆ Supported by research grants from the National Institutes of Health (National Cancer Institute- Early Detection Research Network 1U01CA11125-01). Presented in abstract form at the 106th Digestive Disease Week Meetings, May 15–19, 2005 in Chicago IL. PII: S0014-5793(05)00623-X doi:10.1016/j.febslet.2005.05.030 © 2005 Federation of European Biochemical Societies | |
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ABSTRACT
