α-Catenin is essential in intestinal adenoma formation

Hiroyuki Shibata, Hiroshi Takano, Masaki Ito, Hisashi Shioya, Morihisa Hirota, Hiroshi Matsumoto, Yuichi Kakudo, Chikashi Ishioka, Tetsu Akiyama, Yumi Kanegae, Izumu Saito, Tetsuo Noda

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

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 α-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-Apc580D/+, somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of α-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc580D/+, suggesting that α-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 α-catenin in late-stage tumorigenesis, the role of α-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of β-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for α-catenin. Thus, α-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.

Original languageEnglish
Pages (from-to)18199-18204
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number46
DOIs
Publication statusPublished - 2007 Nov 13

Keywords

  • APC
  • Modifier

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'α-Catenin is essential in intestinal adenoma formation'. Together they form a unique fingerprint.

Cite this