The C-terminus of Apc does not influence intestinal adenoma development or progression.
Adenomatous polyposis coli (APC ) mutations are found in most colorectal tumours. These mutations are almost always protein-truncating, deleting both central domains that regulate Wnt signalling and C-terminal domains that interact with the cytoskeleton. The importance of Wnt dysregulation for colorectal tumourigenesis is well characterized. It is, however, unclear whether loss of C-terminal functions contributes to tumourigenesis, although this protein region has been implicated in cellular processes--including polarity, migration, mitosis, and chromosomal instability (CIN)—that have been postulated as critical for the development and progression of intestinal tumours. Since almost all APC mutations in human patients disrupt both central and C-terminal regions, we created a mouse model to test the role of the C-terminus of APC in intestinal tumourigenesis. This mouse (Apc(ΔSAMP)) carries an internal deletion within Apc that dysregulates Wnt by removing the beta-catenin-binding and SAMP repeats, but leaves the C-terminus intact. We compared Apc(ΔSAMP) mice with Apc(1322T) animals. The latter allele represented the most commonly found human APC mutation and was identical to Apc(ΔSAMP) except for absence of the entire C-terminus. Apc(ΔSAMP) mice developed numerous intestinal adenomas indistinguishable in number, location, and dysplasia from those seen in Apc(1322T) mice. No carcinomas were found in Apc(ΔSAMP) or Apc(1322T) animals. While similar disruption of the Wnt signalling pathway was observed in tumours from both mice, no evidence of differential C-terminus functions (such as cell migration, CIN, or localization of APC and EB1) was seen. We conclude that the C-terminus of APC does not influence intestinal adenoma development or progression.
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. lewisa@well.ox.ac.uk
Annabelle
A
Lewis
Hayley
H
Davis
Maesha
M
Deheragoda
Patrick
P
Pollard
Emma
E
Nye
Rosemary
R
Jeffery
Stefania
S
Segditsas
Philip
P
East
Richard
R
Poulsom
Gordon
G
Stamp
Nicholas
N
Wright
Ian
I
Tomlinson
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway
D025601:Adenomatous Polyposis Coli Protein