Review
Transcriptional Repression by Nuclear Hormone Receptors

https://doi.org/10.1016/S1043-2760(99)00215-5Get rights and content

Abstract

Repression by nuclear receptors plays important roles in acute promyelocytic leukemia and other diseases. Nuclear receptor corepressor (N-CoR) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are corepressor proteins whose modular structure facilitates receptor interaction as well as transduction of repression signals involving histone deacetylation, alterations in chromatin structure and direct interactions with the basal transcription machinery. Interactions between nuclear receptors and corepressor complexes have multiple determinants. This allows regulation, and potentially therapeutic manipulation, of receptor, corepressor, cell-type and target-gene specificity.

Section snippets

Biological/Pathological Significance of Repression by Nuclear Receptors

The ability of nuclear receptors to bind and repress target genes in the absence of ligand serves to amplify the activating effect of hormonal signals. There is abundant and long-standing evidence for a biological role for the hormonal activation of nuclear receptors, but only recently has the importance of basal repression been appreciated. Initial clues came from the study of acute promyelocytic leukemia (APL). APL is associated with rearrangements of the gene encoding RAR-α (RARA), which

Corepressors Mediate Transcriptional Repression by Nuclear Receptors

Repression is mediated by limiting cellular proteins that are recruited to the C-terminal LBD of the receptor14. These proteins, termed corepressors, must fulfill four important criteria, namely: (1) interaction with the unliganded receptor; (2) dissociation upon receptor binding of activating ligand; (3) potentiation of receptor repression; and (4) intrinsic ability to repress transcription of genes to which they are recruited. Two proteins that fulfill these criteria have been cloned and well

Corepressor Determinants of Receptor Interaction

The nuclear receptor-interacting domain has been mapped to the C- terminal regions of N-CoR and SMRT (Fig. 1). Two separate interaction domains (ID1 and ID2; Fig. 1) have been identified23, 24, 25. Interestingly, two nuclear receptor LBDs (either as heterodimers with RXR or as homodimers) are required for corepressor interaction26. Thus, it is possible that each ID contacts one nuclear receptor LBD. In support of this model, the two IDs differ in their affinities for specific receptors. For

Nuclear Receptor Determinants of Interaction with N-CoR and SMRT

The crystal structures of the LBDs of unliganded RXR, liganded RAR, TR, the estrogen receptor (ER) (reviewed in Ref. 29) and peroxisome proliferator-activator receptor-γ (PPAR-γ) (Ref. 30) have been solved. The overall structures of these LBDs are very similar, suggesting a canonical structure for the LBDs of nuclear receptors. The basic structure consists of 12 α-helices (H1–H12). A small region within H1, termed the CoR-box, is required for the interaction with N-CoR and SMRT (Ref. 15).

H12 Regulates Nuclear Receptor Interaction with N-CoR and SMRT

In the unliganded RXR, the last helix (H12) extends into the solvent at an angle of ∼45° away from the core structure34. In sharp contrast, in the liganded LBD structure, H12 is packed onto the core structure, forming the ‘lid’ of the binding pocket (reviewed in Ref. 29). This structural difference suggests that H12 changes position upon ligand binding. Interestingly, H12 is also required for dissociation of corepressors. The oncogenic TR mutant protein, v-ErbA, which lacks H12, has strong

Mechanisms of Repression Signals Transduced by N-CoR and SMRT

The N-terminal region of N-CoR contains at least three transferable repression domains (RD1, RD2 and RD3; Fig. 1)41. The lack of homology of these multiple domains to one another and their conservation in SMRT suggest multiple non-redundant mechanisms for repression involving the corepressors. RD1 and a region downstream of RD3 have been shown to recruit histone deacetylases (HDAC1 and HDAC2) through direct interaction with mSin3A or mSin3B proteins42, 43, 44. Hypoacetylation of histone

Regulation of Repression by Receptors

A variety of mechanisms regulate repression and interaction of specific nuclear receptors with N-CoR and SMRT. As mentioned, the receptor and corepressor interaction domains have inherent specificities. Post-translational modification of receptors or corepressors might alter these interactions49. Moreover, activation of tyrosine kinase signaling disrupts interaction of SMRT with TR as well as PLZF, suggesting that SMRT is the target for phosphorylation50.

Regulation also occurs at the level of

Perspectives and Future Directions

N-CoR and SMRT are related proteins involved in repression of basal transcription by nuclear hormone receptors, as well as other classes of transcription factors. Although it is possible that they serve redundant functions for some nuclear receptors, there is clear specificity, the biological relevance of which might be revealed by studies of organisms with targeted gene deletions. The current model of repression highlights the role of the HDAC–Sin3 complex. It will be interesting to determine

Acknowledgements

This work was supported in part by NIH grants DK43806 and DK45586. We thank Jinsong Zhang for valuable discussion.

References (54)

  • R.J. Lin

    Role of the histone deacetylase complex in acute promyelocytic leukaemia

    Nature

    (1998)
  • V. Gelmetti

    Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO

    Mol. Cell. Biol.

    (1998)
  • B. Lutterbach

    ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors

    Mol. Cell. Biol.

    (1998)
  • J. Wang

    ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • P. Ciana

    Leukemic transformation by the v-ErbA oncoprotein entails constitutive binding of an erythroid enhancer in vivo

    EMBO J.

    (1998)
  • S.M. Yoh

    Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors

    Mol. Endocrinol.

    (1997)
  • J.D. Safer

    Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone

    Mol. Endocrinol.

    (1997)
  • S. Gothe

    Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary–thyroid axis, growth, and bone maturation

    Genes Dev.

    (1999)
  • A. Baniahmad

    The τ4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing

    Mol. Cell. Biol.

    (1995)
  • A.J. Horlein

    Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

    Nature

    (1995)
  • J.D. Chen et al.

    A transcriptional co-repressor that interacts with nuclear hormone receptors

    Nature

    (1995)
  • H-Y. Kao

    A histone deacetylase corepressor complex regulates the Notch signal transduction pathway

    Genes Dev.

    (1998)
  • P. Ordentlich

    Unique forms of human and mouse nuclear receptor corepressor SMRT

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • E.J. Park

    SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • U. Dressel

    Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily

    Mol. Cell. Biol.

    (1999)
  • I. Zamir

    Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • I. Zamir

    A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with different repression domains

    Mol. Cell. Biol.

    (1996)
  • Cited by (243)

    • Thyroid hormone regulation of adult hippocampal neurogenesis: Putative molecular and cellular mechanisms

      2022, Vitamins and Hormones
      Citation Excerpt :

      At positive TREs, unliganded aporeceptor activity leads to complexing with co-repressors that inhibit transcription, and in the presence of the ligand, the holoreceptor recruits coactivators and RNA polymerase II to drive an increase in transcription of the thyroid hormone target gene (Bernal, 2007; Cheng et al., 2010). In contrast, at negative TREs it is the aporeceptor that enhances gene expression, and on binding to the ligand the holoreceptor recruits co-repressors and inhibits transcription of the target gene (Astapova & Hollenberg, 2013; Flamant & Gauthier, 2013; Harvey et al., 2002; Hu & Lazar, 2000; Privalsky, 2004). Apart from the genomic mode of action, non-genomic actions of thyroid hormone are mediated by membrane receptors for thyroid hormone, namely the integrin αVβ3 which is reported to have a binding site for T3, and is thought to mediate rapid actions of thyroid hormone via recruitment of signaling pathways including MAPK signaling, mTOR-p70S6K, and PI3-kinase, along with the alterations of Na+/H+ antiporter activity and changes in actin polymerization (Alisi, Spagnuolo, Napoletano, Spaziani, & Leoni, 2004; Bergh et al., 2005; Cao, Kambe, Moeller, Refetoff, & Seo, 2005; D’Arezzo et al., 2004; Furuya, Lu, Guigon, & Cheng, 2009; Incerpi, Luly, De Vito, & Farias, 1999).

    • Regulation of cardiac transcription by thyroid hormone and Med13

      2019, Journal of Molecular and Cellular Cardiology
    • Thyroid Hormone and Skeletal Development

      2018, Vitamins and Hormones
    View all citing articles on Scopus
    View full text