The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes.

The APC tumor suppressor controls the stability and nuclear export of beta-catenin (beta-cat), a transcriptional coactivator of LEF-1/TCF HMG proteins in the Wnt/Wg signaling pathway. We show here that beta-cat and APC have opposing actions at Wnt target genes in vivo. The beta-cat C-terminal activation domain associates with TRRAP/TIP60 and mixed-lineage-leukemia (MLL1/MLL2) SET1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes H3K4 trimethylation at the c-Myc gene in vivo. H3K4 trimethylation in vivo requires prior ubiquitination of H2B, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits Pygopus, Bcl-9/Legless, and MLL/SET1-type complexes to the c-Myc enhancer together with the negative Wnt regulators, APC, and betaTrCP. Interestingly, APC-mediated repression of c-Myc transcription in HT29-APC colorectal cancer cells is initiated by the transient binding of APC, betaTrCP, and the CtBP corepressor to the c-Myc enhancer, followed by stable binding of the TLE-1 and HDAC1 corepressors. Moreover, nuclear CtBP physically associates with full-length APC, but not with mutant SW480 or HT29 APC proteins. We conclude that, in addition to regulating the stability of beta-cat, APC facilitates CtBP-mediated repression of Wnt target genes in normal, but not in colorectal cancer cells.

[1]  Michael K. Coleman,et al.  A Mammalian Chromatin Remodeling Complex with Similarities to the Yeast INO80 Complex* , 2005, Journal of Biological Chemistry.

[2]  R. Roeder,et al.  The human homolog of yeast BRE1 functions as a transcriptional coactivator through direct activator interactions. , 2005, Molecular cell.

[3]  Paul Tempst,et al.  Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. , 2005, Molecular cell.

[4]  R. Deshaies,et al.  A putative stimulatory role for activator turnover in gene expression , 2005, Nature.

[5]  J. Hess,et al.  MLL associates specifically with a subset of transcriptionally active target genes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Billadeau,et al.  The Ezh2 methyltransferase complex: actin up in the cytosol. , 2005, Trends in cell biology.

[7]  A. Shilatifard,et al.  Molecular regulation of histone H3 trimethylation by COMPASS and the regulation of gene expression. , 2005, Molecular cell.

[8]  C. Allis,et al.  Taking LSD1 to a New High , 2005, Cell.

[9]  K. Basler,et al.  Pygopus and Legless Provide Essential Transcriptional Coactivator Functions to Armadillo/β-Catenin , 2005, Current Biology.

[10]  Thomas A. Milne,et al.  Physical Association and Coordinate Function of the H3 K4 Methyltransferase MLL1 and the H4 K16 Acetyltransferase MOF , 2005, Cell.

[11]  Thomas A. Milne,et al.  WDR5 Associates with Histone H3 Methylated at K4 and Is Essential for H3 K4 Methylation and Vertebrate Development , 2005, Cell.

[12]  Richard A Young,et al.  Global and Hox-specific roles for the MLL1 methyltransferase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Mellor,et al.  Dynamic lysine methylation on histone H3 defines the regulatory phase of gene transcription. , 2005, Molecular cell.

[14]  Mark Peifer,et al.  Decisions, decisions: beta-catenin chooses between adhesion and transcription. , 2005, Trends in cell biology.

[15]  H. Clevers,et al.  Wnt signaling in the intestinal epithelium: from endoderm to cancer. , 2005, Genes & development.

[16]  Hee June Choi,et al.  Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes , 2005, Nature.

[17]  H. Clevers,et al.  Wnt signalling in stem cells and cancer , 2005, Nature.

[18]  J. Workman,et al.  The Mammalian YL1 Protein Is a Shared Subunit of the TRRAP/TIP60 Histone Acetyltransferase and SRCAP Complexes* , 2005, Journal of Biological Chemistry.

[19]  Hans Clevers,et al.  Self-Renewal and Cancer of the Gut: Two Sides of a Coin , 2005, Science.

[20]  Mariann Bienz,et al.  β-Catenin: A Pivot between Cell Adhesion and Wnt Signalling , 2005, Current Biology.

[21]  C. Allis,et al.  Taking LSD 1 to a new high. , 2005, Cell.

[22]  M. Bienz,et al.  The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. , 2004, Developmental cell.

[23]  Mariann Bienz,et al.  Adenomatous polyposis coli proteins and cell adhesion. , 2004, Current opinion in cell biology.

[24]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[25]  K. Basler,et al.  Identification and in vivo role of the Armadillo-Legless interaction , 2004, Development.

[26]  Nam-Chul Ha,et al.  Mechanism of Phosphorylation-Dependent Binding of APC to β-Catenin and Its Role in β-Catenin Degradation , 2004 .

[27]  D. Kimelman,et al.  Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. , 2004, Molecular cell.

[28]  E. Wieschaus,et al.  A nuclear escort for β-catenin , 2004, Nature Cell Biology.

[29]  W. Herr,et al.  Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin To Regulate Hox Gene Expression , 2004, Molecular and Cellular Biology.

[30]  M. Bienz,et al.  Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function , 2004, Nature Cell Biology.

[31]  R. Nusse,et al.  Convergence of Wnt, ß-Catenin, and Cadherin Pathways , 2004, Science.

[32]  E. Ezhkova,et al.  Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3. , 2004, Molecular cell.

[33]  E. Fearon,et al.  TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. , 2003, Cancer research.

[34]  D. Kimelman,et al.  Crystal structure of a beta-catenin/axin complex suggests a mechanism for the beta-catenin destruction complex. , 2003, Genes & development.

[35]  Nicholas Proudfoot,et al.  Isw1 Chromatin Remodeling ATPase Coordinates Transcription Elongation and Termination by RNA Polymerase II , 2003, Cell.

[36]  Stuart L Schreiber,et al.  Methylation of histone H3 K4 mediates association of the Isw1p ATPase with chromatin. , 2003, Molecular cell.

[37]  T. Parmely,et al.  Identification of New Subunits of the Multiprotein Mammalian TRRAP/TIP60-containing Histone Acetyltransferase Complex* , 2003, Journal of Biological Chemistry.

[38]  C. Lima.  CUE'd up for Monoubiquitin , 2003, Cell.

[39]  Michael Hampsey,et al.  Tails of Intrigue Phosphorylation of RNA Polymerase II Mediates Histone Methylation , 2003, Cell.

[40]  Yang Shi,et al.  Coordinated histone modifications mediated by a CtBP co-repressor complex , 2003, Nature.

[41]  Paola Briata,et al.  Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Mariann Bienz,et al.  Nuclear export of the APC tumour suppressor controls β‐catenin function in transcription , 2003, The EMBO journal.

[43]  H. Clevers,et al.  Armadillo/β-catenin signals in the nucleus – proof beyond a reasonable doubt? , 2003, Nature Cell Biology.

[44]  M. Muratani,et al.  How the ubiquitin–proteasome system controls transcription , 2003, Nature Reviews Molecular Cell Biology.

[45]  T. Noda,et al.  Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc. , 2003, Cancer research.

[46]  亨 佐々木.  Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor-β-induced repression of c-myc , 2003 .

[47]  Toshiki Mori,et al.  ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. , 2002, Molecular cell.

[48]  F. Fagotto,et al.  The ins and outs of APC and β‐catenin nuclear transport , 2002 .

[49]  K. Cadigan.  Wnt signaling--20 years and counting. , 2002, Trends in genetics : TIG.

[50]  Mariann Bienz,et al.  The subcellular destinations of apc proteins , 2002, Nature Reviews Molecular Cell Biology.

[51]  G. Chinnadurai,et al.  CtBP, an unconventional transcriptional corepressor in development and oncogenesis. , 2002, Molecular cell.

[52]  P. Farnham,et al.  Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. , 2002, Methods.

[53]  K. Jones,et al.  Chromatin-specific regulation of LEF-1-beta-catenin transcription activation and inhibition in vitro. , 2001, Genes & development.

[54]  S. Jia,et al.  Transcriptional repression: the long and the short of it. , 2001, Genes & development.

[55]  H Clevers,et al.  The chromatin remodelling factor Brg‐1 interacts with β‐catenin to promote target gene activation , 2001, The EMBO journal.

[56]  Raymond L. White,et al.  APC‐mediated downregulation of β‐catenin activity involves nuclear sequestration and nuclear export , 2000, EMBO reports.

[57]  A. Bauer,et al.  Pontin52 and Reptin52 function as antagonistic regulators of β‐catenin signalling activity , 2000, The EMBO journal.

[58]  E Yoshida,et al.  Regulation of Lef-mediated Transcription and p53-dependent Pathway by Associating β-Catenin with CBP/p300* , 2000, The Journal of Biological Chemistry.

[59]  B. Cullen,et al.  Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Mariann Bienz,et al.  The APC tumour suppressor has a nuclear export function , 2000, Nature.

[61]  Kris Vleminckx,et al.  The p300/CBP acetyltransferases function as transcriptional coactivators of β‐catenin in vertebrates , 2000, The EMBO journal.

[62]  A. Bauer,et al.  Pontin52, an interaction partner of beta-catenin, binds to the TATA box binding protein. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[63]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[64]  K. Kinzler,et al.  Apoptosis and APC in colorectal tumorigenesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.