Down-regulation of the tumor suppressor gene C-terminal Src kinase: an early event during premalignant colonic epithelial hyperproliferation.
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.
Kunte
Dhananjay P
DP
Department of Internal Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201, USA.
Wali
Ramesh K
RK
Koetsier
Jennifer L
JL
Hart
John
J
Kostjukova
Maria N
MN
Kilimnik
Anna Y
AY
Pyatkin
Ilia G
IG
Strelnikova
Svetlana R
SR
Roy
Hemant K
HK
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
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