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Short Communications |
From the Department of Surgery,*
Division of Orthopaedic
Surgery, The Hospital for Sick Children and The University of Toronto
Faculty of Medicine; Programme in Genetics and Genomic
Biology,
Research Institute of The Hospital
for Sick Children; and the Department of Laboratory Medicine and
Pathobiology,
Mount Sinai Hospital and
University of Toronto Faculty of Medicine, Toronto, Ontario, Canada
Aggressive fibromatosis is a monoclonal proliferation of spindle
(fibroblast-like) cells. A subset of lesions contain somatic truncating
adenomatous polyposis coli (APC) gene mutations,
and all of the lesions contain an elevated ß-catenin protein level. A
major function of APC is to regulate ß-catenin protein level.
ß-Catenin has a dual function in the cell: it is a member of the
adherens junction, and it binds transcription factors in the
tcf-lef family, transactivating transcription. Cell cultures
from aggressive fibromatoses containing an APC mutation
were studied. Transient transfection of the full-length APC
gene caused decreased proliferation and ß-catenin protein level in
these cultures. To determine whether ß-catenin protein level was
responsible for the change in proliferation rate, stable
transfections of 
N89ß-catenin (a stabilized form that is not
degraded by APC, but retains all other functions) were achieved
in half of the cultures derived from each tumor, whereas the
other half were transfected with an empty vector. Transfection of the
full-length APC gene in cultures that were stably
transfected with N89ß-catenin did not result in a change in
proliferation. The type I promotor of p56lck contains an HMG consensus
region, to which members of the tcf-lef family can bind. p56lck
was expressed in cultures not transfected with the full-length
APC gene and in cultures transfected with the full-length
APC gene and N89ß-catenin, but not in cultures
transfected with only the full-length APC gene. These data
show that APC truncating mutations give aggressive
fibromatosis cells a proliferative advantage through ß-catenin and
suggest that ß-catenin acts to transactivate
transcription.
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