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HIC1 attenuates Wnt signaling by recruitment TCF-4 and -catenin to the nuclear bodies EMBO Journal (2006)

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Wnt signaling in the nucleus Wnt Off Wnt On Wnt Off (negative feedback) (Xi He et al, Development, 2006) Groucho HDAC

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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, -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)

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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)

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What is the nuclear body ? -The nuclear body is a discrete nuclear structure -Cells typically contain 1030 nuclear bodies per nucleus -Each nuclear body has a unique function (P. pandolfi et al, Nat cell biol, 2000)

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HIC1 sequesters TCF-4 into nuclear bodies BTB/POZ : protein-protein interaction CtBP : CtBP binding domain (GLDLSKK)

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CtBP is required for efficient sequestration of TCF-4

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TCF-4 binds directly to HIC1 in vitro

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TCF-4 C-terminal HIC1-N-term HIC1-C-term HIC1-internal ?

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TCF-4 binds directly to HIC1 in vivo

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HIC1 inhibits TCF/ -catenin driven transcription 293 T cell Dimerizer regulated gene expression (Roy pollock et al, Curr opinion, 2002)

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HIC1 inhibits TCF/ -catenin driven transcription

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HIC1 diverts TCF/ -catenin from the WRP

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Physiological meaning of HIC1 Regulating maximum limit of gene expression? CtBP interacts with many of HATs HDAC activity?

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