Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase.
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.
Nagy
L
L
The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Kao
H Y
HY
Chakravarti
D
D
Lin
R J
RJ
Hassig
C A
CA
Ayer
D E
DE
Schreiber
S L
SL
Evans
R M
RM
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; C012589:trichostatin A; D014212:Tretinoin; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex