Inke Näthke - Overview
The Adenomatous Polyposis Coli protein (APC) is implicated
in familial and sporadic colon cancer. APC is one component of a large
protein complex that regulates the degradation of beta-catenin. Beta-catenin
is not only an important regulator of cell adhesion mediated by cadherins,
but also regulates the activity of TCF/Lef type transcription factors,
which regulate the expression of proliferative genes. Thus the amount
of beta-catenin available in the cytoplasm can affect the transcription
of a number of genes including cyclin D1 and c-myc.
Many of the truncated forms of APC found in colonic tumours of patients,
are unable to target beta-catenin for degradation and the resulting increase
in the activity of TCF/Lef partly explains the transformation that results
from such APC mutations. However, evidence is mounting supporting the
importance of additional functions of APC. Its ability to regulate the
cytoskeletal may be particularly important. APC binds directly and indirectly
to microtubules and increases their stability. In interphase, APC accumulates
at dynamic microtubule ends in actively migrating areas of epithelial
cells. In mitosis, APC localises to microtubule ends embedded in kinetochores
where mitotic spindles are attached to chromosomes. These observations
suggest that APC is involved in stabilising microtubules that are required
for cell migration in interphase and microtubules that help to anchor
chromosome to mitotic spindles in mitosis. Consistent with this hypothesis,
cells lacking APC migrate less efficiently and show a significantly higher
incidence of failures in chromosome segregation. A role for APC in both,
cell migration and chromosome segregation may explain why loss of APC
leads to the development of cancer: A decrease in cell migration could
contribute to colon cancer because it leads to an increase in the time
cells spend in the toxic (mutagenic) environment of the gut and aneuploidy
is a common mechanism for the development of cancers and many colonic
tumours are aneuploid.
APC may also affect the actin cytoskeleton since a number of proteins
that can bind to APC also bind to actin. Little is known about the role
of the interactions of APC with such actin binding proteins, however,
our own data and that of others have confirmed that APC can interact with
both, f-actin and microtubules in cells and that the distribution of APC
between these two pools is finely tuned depending on the requirement of
the cell. These observations suggest that APC may be an important co-ordinator
for microtubule and f-actin networks.
The goal of work in my laboratory is to elucidate how APC regulates cytoskeletal
organisation and how loss of this function contributes to the highly penetrant
phenotype of APC mutations. One long-term goal of our studies is the identification
of small molecules that could be used to reconstitute specific functions
of APC in cells lacking APC.
