Ligand-Dependent Nuclear Receptor Corepressor LCoR Functions by Histone Deacetylase-Dependent and -Independent Mechanisms

Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Molecular Cell (Impact Factor: 14.02). 02/2003; 11(1):139-50. DOI: 10.1016/S1097-2765(03)00014-5
Source: PubMed


LCoR (ligand-dependent corepressor) is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LXXLL motif. LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2. Repression by LCoR is abolished by histone deacetylase inhibitor trichostatin A in a receptor-dependent fashion, indicating HDAC-dependent and -independent modes of action. LCoR binds directly to specific HDACs in vitro and in vivo. Moreover, LCoR functions by recruiting C-terminal binding protein corepressors through two consensus binding motifs and colocalizes with CtBPs in the nucleus. LCoR represents a class of corepressor that attenuates agonist-activated nuclear receptor signaling by multiple mechanisms.

Download full-text


Available from: Karen Nygard
  • Source
    • "302 to 433) of LCoR (Figure 1C; note that the GST fusions of truncated LCoR mutants were produced in bacteria at far higher levels than GST fused to full-length LCoR). The 302-433 region of LCoR identified is distinct from the central domain required for interaction with HDACs (6) and the tandem N-terminal PXDLS consensus motifs required for binding of CtBP corepressors (5). Finally, as KAP-1 interacts with C2H2 zinc-finger TF ZBRK1, which functions as a transcriptional repressor in MCF-7 cells (15), we were interested in determining whether LCoR was a component of a KAP-1/ZBRK1 complex. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We identified a novel interaction between ligand-dependent corepressor (LCoR) and the corepressor KRAB-associated protein-1 (KAP-1). The two form a complex with C2H2 zinc-finger transcription factor ZBRK1 on an intronic binding site in the growth arrest and DNA-damage-inducible α (GADD45A) gene and a novel site in the fibroblast growth factor 2 (FGF2) gene. Chromatin at both sites is enriched for histone methyltransferase SETDB1 and histone 3 lysine 9 trimethylation, a repressive epigenetic mark. Depletion of ZBRK1, KAP-1 or LCoR led to elevated GADD45A and FGF2 expression in malignant and non-malignant breast epithelial cells, and caused apoptotic death. Loss of viability could be rescued by simultaneous knockdowns of FGF2 and transcriptional coregulators or by blocking FGF2 function. FGF2 was not concurrently expressed with any of the transcriptional coregulators in breast malignancies, suggesting an inverse correlation between their expression patterns. We propose that ZBRK1, KAP-1 and LCoR form a transcriptional complex that silences gene expression, in particular FGF2, which maintains breast cell viability. Given the broad expression patterns of both LCoR and KAP-1 during development and in the adult, this complex may have several regulatory functions that extend beyond cell survival, mediated by interactions with ZBRK1 or other C2H2 zinc-finger proteins.
    Full-text · Article · May 2014 · Nucleic Acids Research
  • Source
    • "SFR1 may antagonize the function of some ligand-dependent co-repressors, such as ligand-dependent corepressor (LCoR) and repressor of estrogen receptor activity (REA), which bind ERα in the presence of E2 [24], [25], [26]. LCoR inhibits ERα transcriptional activity in a dose-dependent fashion by recruiting co-repressors HDAC3 and CtBP to ERα. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Estrogen receptor alpha (ERα), a ligand-dependent transcription factor, mediates the expression of its target genes by interacting with corepressors and coactivators. Since the first cloning of SRC1, more than 280 nuclear receptor cofactors have been identified, which orchestrate target gene transcription. Aberrant activity of ER or its accessory proteins results in a number of diseases including breast cancer. Here we identified SFR1, a protein involved in DNA homologous recombination, as a novel binding partner of ERα. Initially isolated in a yeast two-hybrid screen, the interaction of SFR1 and ERα was confirmed in vivo by immunoprecipitation and mammalian one-hybrid assays. SFR1 co-localized with ERα in the nucleus, potentiated ER's ligand-dependent and ligand-independent transcriptional activity, and occupied the ER binding sites of its target gene promoters. Knockdown of SFR1 diminished ER's transcriptional activity. Manipulating SFR1 expression by knockdown and overexpression revealed a role for SFR1 in ER-dependent and -independent cancer cell proliferation. SFR1 differs from SRC1 by the lack of an intrinsic activation function. Taken together, we propose that SFR1 is a novel transcriptional modulator for ERα and a potential target in breast cancer therapy.
    Full-text · Article · Jul 2013 · PLoS ONE
  • Source
    • "Also, the regulation of these enzymes during cell cycle and proliferation is largely unknown. HDAC2 is found in large protein complexes, which are associated with nuclear receptor corepressor and ligand-dependent corepressor , such as NuRD and mSin3 [Zhang et al., 1999; Fernandes et al., 2003]. A previous study has suggested that increased HDAC2 expression was found and is enhanced by loss of APC in human colorectal cancer [Zhu et al., 2004]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses, and is often significantly overexpressed in solid tumors, but little is known of its role in human lung cancer. In this study, we demonstrated the aberrant expression of HDAC2 in lung cancer tissues and investigated oncogenic properties of HDAC2 in human lung cancer cell lines. HDAC2 inactivation resulted in regression of tumor cell growth and activation of cellular apoptosis via p53 and Bax activation and Bcl2 suppression. In cell cycle regulation, HDAC2 inactivation caused induction of p21WAF1/CIP1 expression, and simultaneously suppressed the expressions of cyclin E2, cyclin D1, and CDK2, respectively. Consequently, this led to the hypophosphorylation of pRb protein in G1/S transition and thereby inactivated E2F/DP1 target gene transcriptions of A549 cells. In addition, we demonstrated that HDAC2 directly regulated p21WAF1/CIP1 expression in a p53-independent manner. However, HDAC1 was not related to p21WAF1/CIP1 expression and tumorigenesis of lung cancer. Lastly, we observed that sustained-suppression of HDAC2 in A549 lung cancer cells attenuated in vitro tumorigenic properties and in vivo tumor growth of the mouse xenograft model. Taken together, we suggest that the aberrant regulation of HDAC2 and its epigenetic regulation of gene transcription in apoptosis and cell cycle components play an important role in the development of lung cancer.
    Full-text · Article · Jun 2012 · Journal of Cellular Biochemistry
Show more