Download - HIC1 attenuates Wnt signaling by recruitment TCF-4 and β -catenin to the nuclear bodies

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Page 1: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 attenuates Wnt signaling by recruitment TCF-4 and β-catenin to the nuclear bodies

EMBO Journal (2006)

Page 2: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

Wnt signaling in the nucleus

Wnt Off

Wnt On

Wnt Off

(negative feedback)

(Xi He et al, Development, 2006)Groucho

HDAC

Page 3: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

Wnt signaling in the nucleus

- In absence of Wnt,

◦ TCF/LEF-1- Bind constitutively to Wnt enhancers

- In presence of Wnt,

it can interact with corepressor, Groucho, HDAC, CBP

it can interact with coactivator, β-catenin, Pygo, Bcl9,

Chromatin remodeling complexes.

◦ CtBP- Transcriptional corepressor and APC-interacting protein

- Binding of CtBP is correlated with the loss of histone modification

(Karl Willert, Genes & Dev, 2006)

Page 4: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

Introduction to HIC1 nuclear protein

◦ HIC1 (Hypermethylated in cancer 1)

- First identified as a tumor suppressor gene frequently epigenetically silenced or deleted in different type of solid tumors

(Herman JD et al, N Eng J Med, 2003)

- Hic +/- mice develop malignant tumor and densely methylated in wild type allele of Hic1 promoter

- CtBP associating protein and redirects CtBP to a specific set of nuclear dot-like structure called HIC1 bodies

(Chen et al, Nat Genet, 2003)

(Deltour et al, MCB, 2002)

Page 5: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

What is the nuclear body ?

- The nuclear body is a discrete nuclear structure

- Cells typically contain 10–30 nuclear bodies per nucleus

- Each nuclear body has a unique function

(P. pandolfi et al, Nat cell biol, 2000)

Page 6: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 sequesters TCF-4 into nuclear bodiesBTB/POZ : protein-protein interaction

CtBP : CtBP binding domain (GLDLSKK)

Page 7: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

CtBP is required for efficient sequestration of TCF-4

Page 8: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

TCF-4 binds directly to HIC1 in vitro

Page 9: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

TCF-4 binds directly to HIC1 in vitro

TCF-4 C-terminal

HIC1-N-term

HIC1-C-term

HIC1-internal

?

Page 10: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

TCF-4 binds directly to HIC1 in vivo

Page 11: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 inhibits TCF/ β-catenin driven transcription

293 T cell Dimerizer regulated gene expression

(Roy pollock et al, Curr opinion, 2002)

Page 12: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 inhibits TCF/ β-catenin driven transcription

Page 13: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 diverts TCF/ β-catenin from the WRP

Page 14: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

HIC1 diverts TCF/ β-catenin from the WRP

Page 15: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies

Physiological meaning of HIC1

Regulating maximum limit of gene expression?

CtBP interacts with many of HATs

HDAC activity?

Page 16: HIC1 attenuates Wnt signaling by recruitment TCF-4 and  β -catenin to the nuclear bodies