title: Cell growth inhibition by the Mad/Max complex through recruitment of histone deacetylase activity.
abstract: BACKGROUND
  The organization of chromatin is crucial for the regulation of gene expression. In particular, both the positioning and properties of nucleosomes influence promoter-specific transcription. The acetylation of core histones has been suggested to alter the properties of nucleosomes and affect the access of DNA-binding transcriptional regulators to promoters. A recently identified mammalian histone deacetylase (HD1) shows homology to the yeast Rpd3 protein, which together with Sin3 affects the transcription of several genes. Mammalian Sin3 proteins interact with the Mad components of the Myc/Max/Mad network of cell growth regulators. Mad/Max complexes may recruit mammalian Rpd3-like enzymes, therefore, directing histone deacetylase activity to promoters and negatively regulating cell growth.
  
  
  RESULTS
  We report the identification of a tetrameric complex composed of Max, Mad1, Sin3B and HD1. This complex has histone deacetylase activity which can be blocked by the histone deacetylase inhibitors trichostatin A and sodium butyrate. The inhibition of cell growth by Mad1 is enhanced by Sin3B and HD1, as measured by colony formation assays. Furthermore, a Mad1-induced block of S-phase progression can be overcome by trichostatin A, as shown in microinjection experiments.
  
  
  CONCLUSIONS
  The recruitment of a histone deacetylase by sequence-specific DNA-binding proteins provides a mechanism by which the state of acetylation of histones in nucleosomes and hence the activity of specific promoters can be influenced. The finding that Mad/Max complexes interact with Sin3 and HD1 in vivo suggests a model for the role of Mad proteins in antagonizing the function of Myc proteins.
authors.affiliation: Institut für Molekularbiologie Medizinische Hochschule Hannover 30623, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sommer
authors.forename: S
authors.initials: S
authors.lastname: Hilfenhaus
authors.forename: A
authors.initials: A
authors.lastname: Menkel
authors.forename: E
authors.initials: E
authors.lastname: Kremmer
authors.forename: C
authors.initials: C
authors.lastname: Seiser
authors.forename: P
authors.initials: P
authors.lastname: Loidl
authors.forename: B
authors.initials: B
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D019556:COS Cells; D002455:Cell Division / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C067850:Myc associated factor X; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C012589:trichostatin A; D006655:Histone Deacetylases