APC inhibits ERK pathway activation and cellular proliferation induced by RAS.
Inactivating mutations in the adenomatous polyposis coli gene (APC), and activating mutations in RAS, occur in a majority of colorectal carcinomas. However, the relationship between these changes and tumorigenesis is poorly understood. RAS-induced activation of the ERK pathway was reduced by overexpressing APC in DLD-1 colorectal cancer cells. ERK activity was increased by Cre-virus-induced Apc knockout in primary Apc(flox/flox) mouse embryonic fibroblasts, indicating that APC inhibits ERK activity. ERK activity was increased by overexpression and decreased by knock down of beta-catenin. The activation of Raf1, MEK and ERK kinases by beta-catenin was reduced by co-expression of APC. These results indicate that APC inhibits the ERK pathway by an action on beta-catenin. RAS-induced activation of the ERK pathway was reduced by the dominant negative form of TCF4, indicating that the ERK pathway regulation by APC/beta-catenin signaling is, at least, partly caused by effects on beta-catenin/TCF4-mediated gene expression. The GTP loading and the protein level of mutated RAS were decreased in cells with reduced ERK activity as a result of APC overexpression, indicating that APC regulates RAS-induced ERK activation at least partly by reduction of the RAS protein level. APC regulates cellular proliferation and transformation induced by activation of both RAS and beta-catenin signaling.
Division of Molecular and Cellular Biology, Department of Biotechnology, Yonsei University, Seoul 120-752, Korea.
Ki-Sook
KS
Park
Soung Hoo
SH
Jeon
Sung-Eun
SE
Kim
Young-Yil
YY
Bahk
Sheri L
SL
Holmen
Bart O
BO
Williams
Kwang-Chul
KC
Chung
Young-Joon
YJ
Surh
Kang-Yell
KY
Choi
D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D018808:Transcription Factor AP-1 / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D025601:Adenomatous Polyposis Coli Protein; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D018808:Transcription Factor AP-1; D051176:beta Catenin; D050807:ets-Domain Protein Elk-1; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins