Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase

• Published in: Cell Vol. 89; no. 3; pp. 373 - 380
• Main Authors: Nagy, Laszlo, Kao, Hung-Ying, Chakravarti, Debabrata, Lin, Richard J, Hassig, Christian A, Ayer, Donald E, Schreiber, Stuart L, Evans, Ronald M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-05-1997
• Subjects: 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; Histone Deacetylase Inhibitors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; HL-60 Cells - cytology; HL-60 Cells - drug effects; HL-60 Cells - enzymology; 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
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80218-4

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.