A Two-Step Model for Colon Adenoma Initiation and Progression Caused by APC Loss

Aberrant Wnt/β-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli ( APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation but that this occurs in the abs...

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Bibliographic Details
Published in:Cell 2009-05, Vol.137 (4), p.623-634
Main Authors: Phelps, Reid A., Chidester, Stephanie, Dehghanizadeh, Somaye, Phelps, Jason, Sandoval, Imelda T., Rai, Kunal, Broadbent, Talmage, Sarkar, Sharmistha, Burt, Randall W., Jones, David A.
Format: Article
Language:English
Subjects:
Adenoma - genetics
Adenoma - metabolism
Adenoma - pathology
Adenomatous Polyposis Coli - pathology
Adenomatous Polyposis Coli Protein - genetics
Alcohol Oxidoreductases - metabolism
Animals
beta Catenin - metabolism
Cell Differentiation
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Danio rerio
DNA-Binding Proteins - metabolism
Gene Expression Regulation, Neoplastic
Humans
HUMDISEASE
Peptide Fragments - metabolism
Proto-Oncogene Proteins c-raf - metabolism
rac1 GTP-Binding Protein - metabolism
ras Proteins - metabolism
Signal Transduction
Zebrafish
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Summary:Aberrant Wnt/β-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli ( APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation but that this occurs in the absence of nuclear β-catenin and increased intestinal cell proliferation. Therefore, loss of APC is insufficient for causing β-catenin nuclear localization. APC mutation-induced intestinal differentiation defects instead depend on the transcriptional corepressor C-terminal binding protein-1 (CtBP1), whereas proliferation defects and nuclear accumulation of β-catenin require the additional activation of KRAS. These findings suggest that, following APC loss, CtBP1 contributes to adenoma initiation as a first step, whereas KRAS activation and β-catenin nuclear localization promote adenoma progression to carcinomas as a second step. Consistent with this model, human FAP adenomas showed robust upregulation of CtBP1 in the absence of detectable nuclear β-catenin, whereas nuclear β-catenin was detected in carcinomas.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2009.02.037