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

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HIC1 attenuates Wnt signaling by recruitment TCF-4 and β -catenin to the nuclear bodies. EMBO Journal (2006). Wnt signaling in the nucleus. Wnt Off. Wnt On. Wnt Off (negative feedback). HDAC. Groucho. (Xi He et al , Development , 2006). ◦ TCF/LEF-1. - PowerPoint PPT Presentation

Transcript of HIC1 attenuates Wnt signaling by recruitment TCF-4 and ² -catenin to the nuclear bodies

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

  • Wnt signaling in the nucleusWnt OffWnt On Wnt Off(negative feedback)(Xi He et al, Development, 2006)GrouchoHDAC

  • Wnt signaling in the nucleus CtBP- Transcriptional corepressor and APC-interacting protein Binding of CtBP is correlated with the loss of histone modification(Karl Willert, Genes & Dev, 2006)

  • 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 promoterCtBP 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)

  • What is the nuclear body ?The nuclear body is a discrete nuclear structureCells typically contain 1030 nuclear bodies per nucleusEach nuclear body has a unique function(P. pandolfi et al, Nat cell biol, 2000)

  • HIC1 sequesters TCF-4 into nuclear bodiesBTB/POZ : protein-protein interactionCtBP : CtBP binding domain (GLDLSKK)

  • CtBP is required for efficient sequestration of TCF-4

  • TCF-4 binds directly to HIC1 in vitro

  • TCF-4 binds directly to HIC1 in vitroTCF-4 C-terminalHIC1-N-termHIC1-C-termHIC1-internal?

  • TCF-4 binds directly to HIC1 in vivo

  • HIC1 inhibits TCF/ -catenin driven transcription293 T cellDimerizer regulated gene expression(Roy pollock et al, Curr opinion, 2002)

  • HIC1 inhibits TCF/ -catenin driven transcription

  • HIC1 diverts TCF/ -catenin from the WRP

  • HIC1 diverts TCF/ -catenin from the WRP

  • Physiological meaning of HIC1Regulating maximum limit of gene expression?CtBP interacts with many of HATsHDAC activity?