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...

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Bibliographic Details
Published in:FEBS letters 2005-07, Vol.579 (17), p.3497-3502
Main Authors: Kunte, Dhananjay P., Wali, Ramesh K., Koetsier, Jennifer L., Hart, John, Kostjukova, Maria N., Kilimnik, Anna Y., Pyatkin, Ilia G., Strelnikova, Svetlana R., Roy, Hemant K.
Format: Article
Language:English
Subjects:
5′bromo 2′deoxyuridine
Animals
AOM
azoxymethane
BrDu
C-terminal Src kinase
Cell Proliferation
Cell Transformation, Neoplastic
Colon - pathology
Colon cancer
Colonic hyperproliferation
Colonic Neoplasms - enzymology
Colonic Neoplasms - genetics
colorectal cancer
CRC
Csk
Down-Regulation
Genes, Tumor Suppressor
HT29 Cells
Humans
Intestinal Mucosa - immunology
Intestinal Mucosa - pathology
Male
MAP kinase
MAP kinase kinase
MAP Kinase Kinase 1 - antagonists & inhibitors
MAP Kinase Kinase 2 - antagonists & inhibitors
MEK
mitogen-activated protein kinase
PCNA
Precancerous Conditions - enzymology
Precancerous Conditions - pathology
proliferating cell nuclear antigen
Protein Kinase Inhibitors - pharmacology
Protein-Tyrosine Kinases - analysis
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Rats
Rats, Inbred F344
RNA Interference
short hairpin-loop RNA
shRNA
Src
src-Family Kinases
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Summary: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.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2005.05.030