title: Down-regulation of the tumor suppressor gene C-terminal Src kinase: an early event during premalignant colonic epithelial hyperproliferation.
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.
authors.affiliation: Department of Internal Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA.
authors.forename: Dhananjay P
authors.initials: DP
authors.lastname: Kunte
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Wali
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Koetsier
authors.forename: John
authors.initials: J
authors.lastname: Hart
authors.forename: Maria N
authors.initials: MN
authors.lastname: Kostjukova
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Kilimnik
authors.forename: Ilia G
authors.initials: IG
authors.lastname: Pyatkin
authors.forename: Svetlana R
authors.initials: SR
authors.lastname: Strelnikova
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Roy
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D019061:src-Family Kinases
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2