TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent.
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.
Mesh Terms:
Amino Acid Motifs, Animals, Binding Sites, Cell Line, Cytoskeleton, Down-Regulation, E-Box Elements, Fibroblasts, Gene Deletion, Gene Expression Regulation, Enzymologic, Genes, Reporter, Histone Deacetylases, Homozygote, Humans, Immediate-Early Proteins, Immunoblotting, Immunoprecipitation, Luciferases, Membrane Proteins, Mice, Models, Biological, Muscles, NIH 3T3 Cells, Osteopontin, Plasmids, Polymerase Chain Reaction, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Sialoglycoproteins, Sin3 Histone Deacetylase and Corepressor Complex, Sp1 Transcription Factor, TCF Transcription Factors, Tetradecanoylphorbol Acetate, Transcription Factor 7-Like 2 Protein, Transcription, Genetic, Transfection, Up-Regulation, beta Catenin
Amino Acid Motifs, Animals, Binding Sites, Cell Line, Cytoskeleton, Down-Regulation, E-Box Elements, Fibroblasts, Gene Deletion, Gene Expression Regulation, Enzymologic, Genes, Reporter, Histone Deacetylases, Homozygote, Humans, Immediate-Early Proteins, Immunoblotting, Immunoprecipitation, Luciferases, Membrane Proteins, Mice, Models, Biological, Muscles, NIH 3T3 Cells, Osteopontin, Plasmids, Polymerase Chain Reaction, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Sialoglycoproteins, Sin3 Histone Deacetylase and Corepressor Complex, Sp1 Transcription Factor, TCF Transcription Factors, Tetradecanoylphorbol Acetate, Transcription Factor 7-Like 2 Protein, Transcription, Genetic, Transfection, Up-Regulation, beta Catenin
J. Biol. Chem.
Date: Dec. 02, 2005
PubMed ID: 16204248
View in: Pubmed Google Scholar
Download Curated Data For This Publication
110090
Switch View:
- Interactions 4