Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase

Cell. 1997 May 2;89(3):373-80. doi: 10.1016/s0092-8674(00)80218-4.

Abstract

The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors. Here we show that SMRT and N-CoR directly interact with mSin3A, a corepressor for the Mad-Max heterodimer and a homolog of the yeast global-transcriptional repressor Sin3p. In addition, we demonstrate that the recently characterized histone deacetylase 1 (HDAC1) interacts with Sin3A and SMRT to form a multisubunit repressor complex. Consistent with this model, we find that HDAC inhibitors synergize with retinoic acid to stimulate hormone-responsive genes and differentiation of myeloid leukemia (HL-60) cells. This work establishes a convergence of repression pathways for bHLH-Zip proteins and nuclear receptors and suggests this type of regulation may be more widely conserved than previously suspected.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Differentiation / drug effects
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / genetics
  • Gene Expression Regulation, Enzymologic / physiology
  • HL-60 Cells / cytology
  • HL-60 Cells / drug effects
  • HL-60 Cells / enzymology
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism
  • Nuclear Receptor Co-Repressor 2
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tretinoin / pharmacology

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Multienzyme Complexes
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • SIN3A transcription factor
  • Transcription Factors
  • trichostatin A
  • Tretinoin
  • Histone Deacetylases