A Novel Nuclear Receptor Corepressor Complex, N-CoR, Contains Components of the Mammalian SWI/SNF Complex and the Corepressor KAP-1

Abstract

Transcriptional silencing by many transcription factors is mediated by the nuclear receptor corepressor (N-CoR). The mechanism by which N-CoR represses basal transcription involves the direct or indirect recruitment of histone deacetylases (HDACs). We have isolated two multiprotein N-CoR complexes, designated N-CoR-1 and N-CoR-2, which possess histone deacetylase activity that is mediated by distinct HDACs. Based on Western blotting using antibodies against known subunits, the only HDAC found in the N-CoR-1 complex was HDAC3. In contrast, N-CoR-2 contained predominantly HDAC1 and HDAC2 as well as several other subunits that are found in the Sin3A⅐HDAC complex. Using mass spectrometry and Western blotting, we have identified several novel components of the N-CoR-1 complex including the SWI/SNF-related proteins BRG1, BAF 170, BAF 155, BAF 47/INI1, and the corepressor KAP-1 that is involved in silencing heterochromatin. Indirect immunofluorescence has revealed that both KAP-1 and N-CoR colocalize throughout the nucleus. These results suggest that N-CoR is found in distinct multiprotein complexes, which are involved in multiple pathways of transcriptional repression.Cellular proliferation and differentiation is critically dependent on the ability of specific DNA-binding transcription factors to activate or repress the transcription of target genes in a coordinated fashion. This is accomplished through transcription factor-mediated recruitment of coactivators and corepressors, which can regulate transcription through the modification of the local chromatin environment and by specifically interacting with components of the core transcriptional machinery (1, 2). The nuclear hormone receptor superfamily provides a unique model to study the mechanism of transcriptional activation and repression and the role of reversible chromatin modification in the control of gene expression. In the absence of ligand, nuclear hormone receptors such as the thyroid hormone (TR) 1 and retinoic acid receptors (RAR) function as potent repressors by interacting with specific corepressor proteins (3, 4). Ligand binding induces a conformational change in these receptors that results in corepressor release and the recruitment of coactivator proteins (2, 5). The nuclear receptor corepressor (N-CoR), and its related family member silencing mediator for retinoid and thyroid hormone receptor (SMRT), were initially identified by yeast two hybrid screening using unliganded TR or RAR as bait, respectively (3, 4). Several lines of evidence suggest that both N-CoR and SMRT mediate the repressive effects of nuclear hormone receptors. First, both N-CoR and SMRT contain two nuclear receptor interaction domains (IDs) in the carboxyl terminus. Molecular characterization of the IDs reveals the presence of a signature CoR box motif that is necessary and sufficient for receptor interaction and ligand-induced release of N-CoR or SMRT (6 -8). More recently, a strong correlation between repression mediated by the TR and recruitment of N-CoR or SMRT have also been ...

KAP1 regulates type I interferon/STAT1-mediated IRF-1 gene expression

“…KAP1 can recruit and coordinate many components involved in gene silencing. KAP1-mediated gene silencing involves the recruitment of the histone deacetylase (HDAC) complex [16][17][18], and binding to a histone methyltransferase [19]. Therefore, KAP1 orchestrates the function of these co-repressor complexes to inhibit the transcription of its target genes.…”

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“…These results suggest that KAP1 may trap STAT3 through STAT3 Ser727 to repress STAT3 transcriptional activation, because STAT3 SA mutant fails to interact with KAP1 as shown in Figure 1d. A direct interaction of KAP1 with HDACs is also proposed to be a mechanism for transcriptional repression by KAP1 (Underhill et al, 2000;Satou et al, 2001;Schultz et al, 2001). It has also been demonstrated that STAT3 associates with HDAC3 and that trichostatin A, an HDAC inhibitor, restores its transcriptional activity (Yuan et al, 2005).…”

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“…KAP1 can recruit and coordinate many components involved in gene silencing. KAP1-mediated gene silencing involves the recruitment of the histone deacetylase complex (HDAC) (Underhill et al, 2000;Satou et al, 2001;Schultz et al, 2001) and binding to a histone methyltransferase (Schultz et al, 2002). Therefore, KAP1 orchestrates the function of these corepressor complexes to inhibit the transcription of its target genes.…”

TIPUH1 encodes a novel KRAB zinc-finger protein highly expressed in human hepatocellular carcinomas

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