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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).

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slide1

Aberrant Wnt / b-catenin signaling can induce

chromosomal instability in colon cancer

Behrens. J et al, PNAS, 2006

slide2

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)

slide3

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)

slide4

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)

slide5

Conductin is up-regulated in CIN tumor

• CIN+ or – is determined by CEP-FISH

•Conductin expression level is determined using RT-PCR

slide7

APC mutation

Wnt signaling On

Conductin

?

CIN

Wnt signaling activation causes CIN via conductin

slide8

Conductin is up-regulated during Mitosis

(Barr F.A. et al, Nat rev, 2004)

slide12

Summary

APC mutation

?

CIN

Spindle checkpoint inactivation

Wnt On

PLK1 activation

• Why APC mutation?

Conductin