title: TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent.
abstract: 12-O-Tetradecanoylphorbol-13-acetate-induced sequence 7 (TIS7) acts as a transcriptional co-repressor interacting with SIN3, the histone deacetylase-containing complex. The overexpression of TIS7 down-regulates expression of a specific set of genes. Homozygous deletion of this gene in mice delays injury-induced muscle regeneration and inhibits muscle satellite cell differentiation and fusion of myoblasts in vitro. Osteopontin (OPN), a known beta-catenin/T cell factor-4 (Tcf-4) downstream target gene, is up-regulated in tumors and in cells with increased motility such as muscle cells. OPN promoter sequence contains binding sites for Sp1, glucocorticoid receptor, E-box-binding factors, octamer motif-binding protein, c-Myc, and other transcription factors. Previously we have shown that TIS7 regulates the OPN expression through the inhibition of the Sp1-activating effects. Here we show that TIS7 has the capacity to inhibit OPN expression also through Lef-1, the second identified OPN regulatory element. TIS7 has the capacity to down-regulate beta-catenin/Tcf-4 transcriptional activity. TIS7 homologous deletion in mouse embryonic fibroblasts increased not only the TOPflash reporter gene transcriptional activity but also the expression of c-Myc and OPN. Furthermore, we show that TIS7 overexpression leads to the beta-catenin interaction with enzymatically active histone deacetylases. We propose that TIS7 down-regulates the beta-catenin/Tcf-4 transcriptional activity via its interaction with histone deacetylase-containing complex thereby inhibiting the expression of beta-catenin downstream target genes such as c-Myc and OPN. We hypothesize that TIS7 as a negative regulator of transcriptional activity represses expression of OPN and beta-catenin/Tcf-4 target genes, which are involved in myogenesis, muscle maintenance, and regeneration in a histone deacetylase dependent manner.
authors.affiliation: Biocenter, Division of Cell Biology, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
authors.forename: Ilja
authors.initials: I
authors.lastname: Vietor
authors.forename: Robert
authors.initials: R
authors.lastname: Kurzbauer
authors.forename: Gerald
authors.initials: G
authors.lastname: Brosch
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D024721:E-Box Elements; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism; D041681:NIH 3T3 Cells; D053495:Osteopontin; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D011965:Receptors, Glucocorticoid; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D016329:Sp1 Transcription Factor; C506896:Spp1 protein, mouse; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D053495:Osteopontin; D008156:Luciferases; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013755:Tetradecanoylphorbol Acetate