Aberrant Wnt / b -catenin signaling can induce

1. Aberrant Wnt / b-catenin signaling can induce chromosomal instability in colon cancer Behrens. J et al, PNAS, 2006

2. 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)

3. 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)

4. 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)

5. Conductin is up-regulated in CIN tumor • CIN+ or – is determined by CEP-FISH •Conductin expression level is determined using RT-PCR

6. Overexpression of conductin causes CIN

7. APC mutation Wnt signaling On Conductin ? CIN Wnt signaling activation causes CIN via conductin

8. Conductin is up-regulated during Mitosis (Barr F.A. et al, Nat rev, 2004)

9. Conductin is up-regulated during Mitosis (continued) (Barr F.A. et al, Nat rev, 2004)

10. Conductin compromises the mitotic spindle checkpoint

11. PLK1 activity is required for the function of conductin (Barr F.A. et al, Nat rev, 2004)

12. Summary APC mutation ? CIN Spindle checkpoint inactivation Wnt On PLK1 activation • Why APC mutation? Conductin