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.

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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. 2000 ) 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. 2003 and Neufeld et al, EMBO Rep. 2000 )

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

hCtBP1 Localized in nucleus and golgi of cytoplasm.

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

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

Bcatenin binding sites

Direct binding between dCtBP and EAPC

APC in mammalian cells

Association between APC and CtBP in mammalian cells

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

Localized in cytoplasm Present in nucleus

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

③

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

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

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.