Somatic Apc mutations are selected upon their capacity to inactivate the beta-catenin downregulating activity.
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(delta 7N) ) 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(delta 7N/delta 7N) 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(delta 7N/delta 7N) /Apc(+/1638N) and Msh2(delta 7N/delta 7N) /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.
Smits
R
R
MGC-Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Hofland
N
N
Edelmann
W
W
Geugien
M
M
Jagmohan-Changur
S
S
Albuquerque
C
C
Breukel
C
C
Kucherlapati
R
R
Kielman
M F
MF
Fodde
R
R
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D017491:Genes, APC / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051176:beta Catenin; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein