1. Function of the APC
1.Reducing the levels of cytoplasmic bcatenin by binding to Axin.
2. Nuclear APC binding to beta-catenin, and then inducing its nuclear export, plays a critical role in the control of nuclear beta-catenin levels and activity.
(Neufeld et al, EMBO Rep )
3. Targeting a functional APC construct to the nucleus causes a striking nuclear accumulation of beta-catenin without changing its transcriptional activity. APC sequester bcatenin, thus keeping it from binding to TCF and activating transcription.
(Rosin-arbesfeld et al, EMBO J and Neufeld et al, EMBO Rep )

2. C-terminal binding protein ( CtBP)
P-h-D-L-S-x-R/K
* Originally identified as a cellular protein which binds to the c-terminal region of AV E1A.
* Highly conserved through specification.
: CtBP1/2 (vertebrates), single CtBP (invertebrates)
*Ctbp1 null mice are viable and are smaller size. Ctbp2 null mice exhibit embryonic lethal phenotype.
Functions as transcriptional corepressors in a histone deactylase-dependent or –independent manner.
Binding to xtcf3. hTcf4 has the CtBP binding motif at c-terminus region.
Chinnaurai G, Mol Cell(Review),2002

3. hCtBP1
Localized in nucleus and golgi of cytoplasm.

4. Valenta T et al, 2003, Nucleic. Acids.Res.

5. Valenta T et al, 2003, Nucleic. Acids.Res.

6. Bcatenin binding sites

8. Direct binding between dCtBP and EAPC

10. APC in mammalian cells

11. Association between APC and CtBP in mammalian cells

12. The Background for Figure.3
Cell lines containing 15R
Rosin-arbesfeld et al, EMBO J. 2003

14. Localized in cytoplasm
Present in nucleus

15. Model :
APC binds to free nuclear bcatenin in competition with TCF and targets bcatenin to CtBP, thus diverting bcatenin away from TCF.
Supporting evidence ② ① ②

16. ③

17. D. Activated arm and mutant dCtBP
G. Depleted arm and mutant dCtBP

19. The mutant is equally responsive to coexpressed CtBP as the wild type TCF-4

21. CONCLUSIONS
CtBP binds to APC directly and specifically via the conserved 15Rs of APC.
interaction between CtBP and APC reduces TCF-mediated transcription in colorectal cancer cells.
CtBP interacts neither physically nor functionally with TCF.
CtBP antagonizes TCF-mediated transcription by cooperating with APC to sequester nuclear bcatenin.