Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes.
Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of beta-catenin, along with a reptin chromatin remodelling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappaB target genes.
Pubmed ID: 15829968 RIS Download
Acetyltransferases | Animals | Antigens, CD | Antigens, CD82 | Cell Line, Tumor | Chromatin Assembly and Disassembly | Collagen | Cytoskeletal Proteins | Down-Regulation | Drug Combinations | Gene Expression Regulation, Neoplastic | Histone Acetyltransferases | Humans | Laminin | Male | Membrane Glycoproteins | Mice | NF-kappa B | Neoplasm Metastasis | Neoplasm Transplantation | Promoter Regions, Genetic | Prostatic Neoplasms | Proteoglycans | Proto-Oncogene Proteins | RNA, Messenger | Trans-Activators | Transcription, Genetic | beta Catenin