Aberrant Wnt / b -catenin signaling can induce
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Aberrant Wnt / Aberrant Wnt / -catenin signaling can induce-catenin signaling can induce
chromosomal instability in colon cancerchromosomal instability in colon cancer
Behrens. J et al, PNAS, 2006
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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)
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What is CIN?
◦ CIN (Chromosomal Instability)
- CIN is defined as an increased rate of loss or gain in
chromosome numbers and parts.
- 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)
Polyploidy + aneuploidy
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Cell cycle check point
◦ G1/S DNA damage check point ◦ G2/M DNA replication check point
◦ Mitotic spindle check point
(Pinsky. B.A. et al, Trends in cell biol, 2005)
Spindle check point On
APC/C is inhibited
Arrested to Metaphase
It is thought that inactivation of spindle checkpoint is a cause of CIN
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Conductin is up-regulated in CIN tumor
• CIN+ or – is determined by CEP-FISH
• Conductin expression level is determined using RT-PCR
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Overexpression of conductin causes CIN
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Wnt signaling activation causes CIN via conductin
APC mutation
Wnt signaling On
Conductin
?
CIN
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Conductin is up-regulated during Mitosis
(Barr F.A. et al, Nat rev, 2004)
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Conductin is up-regulated during Mitosis (continued)
(Barr F.A. et al, Nat rev, 2004)
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Conductin compromises the mitotic spindle checkpoint
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PLK1 activity is required for the function of conductin
(Barr F.A. et al, Nat rev, 2004)
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Summary
APC mutation
Conductin
Wnt On
PLK1 activation
Spindle checkpoint inactivation
CIN
?
• Why APC mutation?