aberrant wnt / -catenin signaling can induce chromosomal instability in colon cancer behrens. j et...

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

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.

- 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

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

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

Conductin

Wnt On

PLK1 activation

Spindle checkpoint inactivation

CIN

?

• Why APC mutation?