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Aberrant Wnt / b-catenin signaling can induce
chromosomal instability in colon cancer
Behrens. J et al, PNAS, 2006
Introduction
◦ The hallmarks of colon tumors
- APC mutation
Mutations in APC are the most frequent events in colon tumors
(Powell, S.M et al, Nature, 1992)
- CIN (Chromosomal Instability)
CIN can cause gross changes in gene expression that in turn
may promote tumorigenesis
(Kops, G.J. et al, Nat. Rev. Cancer, 2005)
What is CIN?
◦ CIN (Chromosomal Instability)
- CIN is defined as an increased rate of loss or gain in
chromosome numbers and parts.
Polyploidy + aneuploidy
- It is believed that causes of CIN is in mitosis
- It has been suggested that mutations in APC can lead CIN
(Kaplan, K. B. et al, Nat cell biol, 2001)
Cell cycle check point
◦ G1/S DNA damage check point ◦ G2/M DNA replication check point
◦ Mitotic spindle check point
Spindle check point On
APC/C is inhibited
Arrested to Metaphase
It is thought that inactivation of
spindle checkpoint is a cause of CIN
(Pinsky. B.A. et al, Trends in cell biol, 2005)
Conductin is up-regulated in CIN tumor
• CIN+ or – is determined by CEP-FISH
• Conductin expression level is determined using RT-PCR
Overexpression of conductin causes CIN
Wnt signaling activation causes CIN via conductin
APC mutation
Wnt signaling On
Conductin
?
CIN
Conductin is up-regulated during Mitosis
(Barr F.A. et al, Nat rev, 2004)
Conductin is up-regulated during Mitosis (continued)
(Barr F.A. et al, Nat rev, 2004)
Conductin compromises the mitotic spindle checkpoint
PLK1 activity is required for the function of conductin
(Barr F.A. et al, Nat rev, 2004)
Summary
APC mutation
?
CIN
Wnt On
Spindle checkpoint
inactivation
PLK1 activation
• Why APC mutation?
Conductin