Reference SummarySmits R, Genes Chromosomes Cancer 2000 Nov;29(3):229-39

Title

Somatic apc mutations are selected upon their capacity to inactivate the beta-catenin downregulating activity

Authors

Smits R; Hofland N; Edelmann W; Geugien M; Jagmohan-Changur S; Albuquerque C; Breukel C; Kucherlapati R; Kielman MF; Fodde R

Journal

Genes Chromosomes Cancer

Volume

29

Issue

3

Year

2000

Pages

229-39

Abstract

The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true 'gatekeeper' of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular beta-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2(Delta7N) ) was generated and bred with Apc(1638N) and Apc(Min) that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2(Delta7N/Delta7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. beta-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2(Delta7N/Delta7N) /Apc(+/1638N) and Msh2(Delta7N/Delta7N) /Apc(+/Min) tumors are clustered more to the 5' end, thereby completely inactivating the beta-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the beta-catenin downregulating function of APC is likely to represent the main selective factor. Copyright 2000 Wiley-Liss, Inc.

Links

J:64667 – Mouse Genome Informatics
10992298 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129P2-Msh2tm1Rak/+ Intestine - Large Intestine - Colon polyp Intestine - Large Intestine - Colon

3.8

B6;129P2-Apctm1Rak/+ Msh2tm1Rak Intestine - Small Intestine tumor Intestine - Small Intestine

100

B6;129P2-ApcMin/+ Msh2tm1Rak Intestine - Small Intestine tumor Intestine - Small Intestine

100

B6;129P2-Msh2tm1Rak Intestine tumor Intestine

72

B6;129P2 Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

6.3

B6;129P2-Msh2tm1Rak/+ Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

35

B6;129P2-Msh2tm1Rak Leukocyte - Lymphocyte lymphoma Leukocyte - Lymphocyte

72

B6;129P2 Liver hepatocellular adenoma Liver

6.3

B6;129P2-Msh2tm1Rak/+ Liver hepatocellular adenoma Liver

12