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Carcinogenesis Advance Access published online on June 1, 2005
Carcinogenesis, doi:10.1093/carcin/bgi145
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received January 10, 2005
Revised May 19, 2005
Accepted May 29, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Ionomycin downregulates {beta}-catenin/Tcf signaling in colon cancer cell line

Chi Hoon Park 1, Eun Ryeong Hahm 1, Ju Hyung Lee 1, Kyung Chae Jung 1, Ho Sung Lee 1, and Chul Hak Yang 1*

1 Division of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, Korea

* To whom correspondence should be addressed.
Chul Hak Yang, E-mail: chulyang{at}plaza.snu.ac.kr


  Abstract

Functional activation of {beta}-catenin/Tcf signaling plays an important role in the early events in colorectal carcinogenesis. We examined the effect of ionomycin against {beta}-catenin/Tcf signaling in colon cancer cells. Reporter gene assay showed that ionomycin inhibited {beta}-catenin/Tcf signaling efficiently. In addition, the inhibition of {beta}-catenin/Tcf signaling by ionomycin in HEK293 cells transiently transfected with a constitutively mutant {beta}-catenin gene, whose product is not phosphorylated by GSK3{beta}, indicates that its inhibitory mechanism is related to {beta}-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed immunoprecipitation analysis, western blot, and EMSA. As a result, our data reveal that the association of {beta}-catenin and Tcf-4 is disrupted and the amount of {beta}-catenin product in the nucleus is decreased by ionomycin in a concentration dependent manner. Moreover, ionomycin strongly suppressed the binding of the Tcf complexes to its specific DNA-binding sites. The significance of the current work is that ionomycin is a negative regulator of {beta}-catenin/Tcf signaling in colon cancer cells and its inhibitory mechanism is related to the decreased nuclear {beta}-catenin products and to the suppressed binding of Tcf complexes to consensus DNA.


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