RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis.
In intestinal epithelial cells, inactivation of APC, a key regulator of the Wnt pathway, activates beta-catenin to initiate tumorigenesis. However, other alterations may be involved in intestinal tumorigenesis. Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with beta-catenin/TCF4 and attenuates Wnt signaling activity. A significant fraction of human sporadic colorectal adenomas and Runx3(+/-) mouse intestinal adenomas showed inactivation of RUNX3 without apparent beta-catenin accumulation, indicating that RUNX3 inactivation independently induces intestinal adenomas. In human colon cancers, RUNX3 is frequently inactivated with concomitant beta-catenin accumulation, suggesting that adenomas induced by inactivation of RUNX3 may progress to malignancy. Taken together, these data demonstrate that RUNX3 functions as a tumor suppressor by attenuating Wnt signaling.
Ito
Kosei
K
Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673.
Lim
Anthony Chee-Beng
AC
Salto-Tellez
Manuel
M
Motoda
Lena
L
Osato
Motomi
M
Chuang
Linda Shyue Huey
LS
Lee
Cecilia Wei Lin
CW
Voon
Dominic Chih-Cheng
DC
Koo
Jason Kin Wai
JK
Wang
Huajing
H
Fukamachi
Hiroshi
H
Ito
Yoshiaki
Y
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D018256:Adenomatous Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D006965:Hyperplasia; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050677:Core Binding Factor Alpha 3 Subunit; D056741:Cyclin D; D016213:Cyclins; D009419:Nerve Tissue Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin