Alpha-catenin is essential in intestinal adenoma formation.
A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line19-Apc(580D/+)) showed a remarkably reduced incidence of intestinal adenomas (<5% compared with other lines). Extensive genetic analysis identified a deletion in the alpha-catenin (Ctnna1) gene as the cause of this suppression. Notably, the suppression only occurred when the Ctnna1 deletion was in cis-configuration with the Apc580D mutation. In all adenomas generated in line19-Apc(580D/+), somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of alpha-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc(580D/+), suggesting that alpha-catenin plays an essential role in the initiation of intestinal adenomas. Although accumulating evidence obtained from human colon tumors with invasive or metastatic potential has established a tumor-suppressive role for alpha-catenin in late-stage tumorigenesis, the role of alpha-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of beta-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for alpha-catenin. Thus, alpha-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.
Shibata
Hiroyuki
H
Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, Tokyo 135-8550, Japan.
Takano
Hiroshi
H
Ito
Masaki
M
Shioya
Hisashi
H
Hirota
Morihisa
M
Matsumoto
Hiroshi
H
Kakudo
Yuichi
Y
Ishioka
Chikashi
C
Akiyama
Tetsu
T
Kanegae
Yumi
Y
Saito
Izumu
I
Noda
Tetsuo
T
D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D010641:Phenotype; D051178:alpha Catenin / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D051178:alpha Catenin