Research Report - Nikolaus-Fiebiger-Zentrum für Molekulare Medizin

and β-catenin phosphorylation oscillates during the cell cycle in a conductindependent
manner. Conductin is degraded by the anaphase-promoting
complex/cyclosome cofactor CDC20. Knockdown of CDC20 blocks Wnt signalling
through conductin. CDC20-resistant conductin inhibits Wnt signalling and attenuates
colony formation of colorectal cancer cells. We propose that CDC20-mediated
degradation of conductin regulates Wnt/β-catenin signalling for maximal activity
during G1/S (Hadjihannas et al., 2012).
We also found that conductin localizes at the centrosomes by binding to the centrioleassociated
component C-Nap1. Knockout or knockdown of conductin leads to
premature centrosome separation which is abolished by knockdown of β-catenin.
Conductin promotes phosphorylation of the amino-terminal serine (Ser 33/37) and
threonine (Thr 41) residues of centrosome-associated β-catenin. β-Catenin mutated
at these residues causes centrosomal separation, whereas a phospho-mimicking
mutant of β-catenin does not. Treatment with Wnts and inhibition of glycogen
synthase kinase 3 block β-catenin phosphorylation and induce centrosomal splitting.
These data indicate that Wnt signalling and conductin regulate centrosomal cohesion
by altering the phosphorylation status of β-catenin at the centrosomes (Hadjihannas
et al., 2010).
Functional dissection of APC mutants truncated in colorectal cancer
Jean Schneickert, Eva Kohler, Shree Harsha Vijaya Chandra
The tumour suppressor Adenomatous Polyposis Coli (APC) is truncated in most
colon cancers, but is not completely lost. It is not clear why colon cancer cells retain
the truncated APC fragment. The mutations affecting both APC alleles are
interdependent, the position of the first APC mutation determining where the second
hit will occur. This results in a complex pattern of mutation distribution in the APC
sequence that translates into the stabilization of β−catenin that in turn feeds the
affected cells with a permanent mitogenic signal. We found a new APC domain, the
β−catenin inhibitory domain (CID) of APC located between the second and third 20
amino acid repeats and therefore present in many truncated APC products found in
human tumours. In truncated APC, the CID is absolutely necessary to down-regulate
the transcriptional activity and the level of β−catenin, even when an axin/conductin
binding site is present (Kohler et al., 2009).
The four 15 amino acid repeats (15R) and the seven 20 amino acid repeats (20R) of
APC are beta-catenin-binding sites, but their role in beta-catenin degradation has
remained unclear. We showed that binding of β-catenin to the 15R of APC is
necessary and sufficient to target β-catenin for degradation. The first 15R displays
the highest affinity for beta-catenin in the 15R-20R module. The analysis of the
distribution of truncating mutations along the APC sequence in colorectal tumours
from FAP patients revealed that the first 15R is one target of the positive selection of
mutations that lead to tumour development (Kohler et al., 2010).
29