Nuclear receptor coregulators

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Nuclear receptor coregulators [1] are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.

Contents

Introduction

The ability of nuclear receptors to alternate between activation and repression in response to specific molecular cues, is now known to be attributable in large part to a diverse group of cellular factors, collectively termed coregulators and including coactivators and corepressors. The study of nuclear receptors owed a debt to decades of historical endocrinology and pathology, and prior to their discovery there was a wealth of empirical evidence that suggested their existence. Coregulators, in contrast, have been the subject of a rapid accumulation of functional and mechanistic data which is yet to be consolidated into an integrated picture of their biological functions. While this article refers to the historical terms "coactivator" and "corepressor," this distinction is less clear than was at first thought, and it is now known that cell type, cell signaling state and promoter identity can influence the direction of action of any given coregulator. [2]

Coregulators are often incorrectly referred to as cofactors, which are small, non-protein molecules required by an enzyme for full activity, e.g. NAD+.

Coactivators

As far back as the early 1970s, receptor-associated nonhistone proteins were known to support the function of nuclear receptors. [3] In the early 1990s, some investigators such as Keith Yamamoto had suggested a role for non-DNA nuclear acceptor molecules. [4] A biochemical strategy designed in Myles Brown's laboratory provided the first direct evidence of ligand-dependent recruitment by nuclear receptors of ancillary molecules. [5]

The yeast two-hybrid protein-protein interaction assay led to the identification of an array of receptor-interacting factors in David Moore's laboratory [6] and RIP140 repressive protein was discovered in Malcolm Parker's laboratory. [7]

The stage was now set for the cloning of the coactivators. The first authentic, common nuclear receptor coactivator was steroid receptor coactivator 1, or SRC-1 (NCOA1), first cloned in Bert O’Malley's laboratory. [8] SRC-1 and two related proteins, GRIP-1 (NCOA2), cloned first by Michael Stallcup, [9] and ACTR/p/CIP (NCOA3), initially identified in Ron Evans [10] and Geoff Rosenfeld's lab, [11] together make up the SRC/NCOA family of coactivators. The SRC family is defined by the presence in the N-terminus of tandem PAS and beta-HLH motifs; a centrally-located domain which binds the coactivators CBP and p300; and a C-terminal region which mediates interaction with the CARM-1 coactivator. Malcolm Parker's laboratory was the first to show that a recurring structural feature of many coactivators is an alpha-helical LXXLL motif (a contiguous sequence of 5 amino acids where L = leucine and X = any amino acid), or nuclear receptor box, present from a single to several copies in many coactivators, which is implicated in their ligand-dependent recruitment by the receptor AF-2. [12] The SRC coactivator family, for example, has a conserved cluster of NR boxes located in the central region of each member of the family.

Coactivators can be categorized based upon their varied functional properties. To name a few, classes of coactivators include:

Corepressors

Transcriptional repression by corepressors is in many ways conceptually comparable to the mediation of receptor transcriptional activation by coactivators, but has an opposite outcome. Recruitment of corepressors, generally occurring in the absence of ligand, depends on a critical conformation of the receptor AF-2 domain, as well as upon nuclear receptor box-like helical motifs in the corepressor. Moreover, corepressors themselves recruit ancillary enzyme activities which help to establish or maintain the repressive state at their target promoters.

Early cell transfection experiments had shown that discrete regions of certain receptors, such as thyroid hormone receptor, were sufficient to repress, or silence, reporter genes when fused to DNA-binding domains of heterologous transcription factors, suggesting that specific cellular factors – or corepressors - might bind to these regions and silence receptors in cells. [19]

Again, using the yeast two-hybrid screen, two corepressors were isolated in rapid succession, nuclear receptor corepressor, or NCoR, in Geoff Rosenfeld's laboratory, [20] and silencing mediator of retinoid and thyroid receptors, or SMRT, by Ron Evans. [21] Alignment of the two proteins indicated that they had a largely common domain structure, suggesting parallels in their mode of action. Mitch Lazar's group has shown that inactive nuclear receptors recruit corepressors in part through amphipathic helical peptides called CoRNR boxes, which are similar to the coactivator nuclear receptor boxes. [22]

In addition to these structural analogies, corepressors and coactivators have common functional themes. The acetylation state of nucleosomes on a promoter is related to the rate of transcription of the gene. Histone acetylase coactivators increase the rate of acetylation, opening the nucleosome to transcription factors; histone deacetylases recruited by corepressors reverse this reaction, silencing transcription of the target gene. [23] Other histone modifications have similar or opposite effects on transcription.

Biology of coregulators

The physiological role of SRC/p160s, CBP/p300 and other coactivators has been implied by knockout studies in mice of genes encoding these proteins. The effects of these deletions range from the profound effects on viability characteristic of TRAP220, CBP and p300, to the more subtle developmental and metabolic phenotypes associated with members of the SRC family. Using sequences from cloned coregulator genes, laboratories such as those led by Bert O’Malley (SRC-1), [24] Bob Roeder (TRAP220), [25] Geoff Rosenfeld (NCoR), [26] and Pierre Chambon (GRIP1) [27] were able to delete, or knockout these genes in mice. These studies showed that coactivators were required for physiological and developmental functions of steroid and thyroid hormones in living animals, and that corepressors too have crucial roles in the development of certain organs.

Regulation of coregulator function

General model for cross-talk between afferent signaling pathways, coregulators and nuclear receptors at a promoter showing local nucleosomal condensation. Promoter.GIF
General model for cross-talk between afferent signaling pathways, coregulators and nuclear receptors at a promoter showing local nucleosomal condensation.

A spectrum of post-translational modifications is known to regulate the functional relationships between nuclear receptors, their coregulator complexes, and their target gene networks. Targeted, reversible enzymatic modifications such as acetylation, [28] methylation [29] phosphorylation [30] and terminal modifications such as ubiquitination [31] have been shown to have a variety of effects on coregulator function. Coregulators may be viewed as control interfaces for integrating multiple afferent stimuli into an appropriate cellular response. One possible scenario is that differential phosphorylation of coactivators may direct their combinatorial recruitment into different transcriptional complexes at distinct promoters in specific cells.

General model

Coactivators exist in large, modular complexes in the cell, [32] and are known to participate in many different protein-protein interactions. A current model is that the composition of these complexes can become fluid, mixing and matching subunits to tailor the specific needs of different receptors, ligands or promoters. While spatiotemporal aspects of nuclear receptor and coregulator action remain poorly defined, a broad composite model of nuclear receptor action invokes corepressors as critical mediators of nuclear receptor silencing. In turn, a variety of coactivators are implicated in transcriptional activation by nuclear receptors, including SWI/SNF chromatin remodeling machines, SRC/p160s and TRAP/DRIP. The model accommodates the ability of membrane G protein coupled signaling pathways and tyrosine receptor signaling to cross-talk with coactivator and corepressor functions at the transcriptional level. [33]

Coregulators and human disease

With the well-documented role of nuclear receptor coregulators in a variety of molecular functions within the cell, it should come as no surprise that evidence implicates them in a wide variety of diseases states, including cancer, metabolic syndromes (obesity, diabetes) and heritable syndromes such as Rubinstein-Taybi Syndrome, Angelman syndrome and Von Gierke's disease. A comprehensive review of the role of coregulators in human disease has been published, [34] which shows that over 165 of the known coregulators have been implicated in human pathologies.

Related Research Articles

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

<span class="mw-page-title-main">Selective progesterone receptor modulator</span> Drug affecting hormone receptors

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists and full antagonists is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Nuclear receptor coactivator 1</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.

<span class="mw-page-title-main">Nuclear receptor coactivator 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 2 also known as NCoA-2 is a protein that in humans is encoded by the NCOA2 gene. NCoA-2 is also frequently called glucocorticoid receptor-interacting protein 1 (GRIP1), steroid receptor coactivator-2 (SRC-2), or transcriptional mediators/intermediary factor 2 (TIF2).

<span class="mw-page-title-main">Nuclear receptor coactivator 3</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).

<span class="mw-page-title-main">Nuclear receptor co-repressor 2</span> Protein-coding gene in the species Homo sapiens

The nuclear receptor co-repressor 2 (NCOR2) is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression. NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT) or T3 receptor-associating cofactor 1 (TRAC-1).

<span class="mw-page-title-main">Bert W. O'Malley</span> American endocrinologist

Bert W. O'Malley is an endocrinologist from the United States. He was born in 1936 in the Garfield section of Pittsburgh, Pennsylvania. He received his early education at Catholic primary schools and Central Catholic High School, before pursuing higher education at the University of Pittsburgh, where he completed both his undergraduate and medical studies, graduating first in his class. It was here that he met Sally, who would become his wife and lifelong partner. The couple went on to have four children.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor alpha (RAR-α), also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">COUP-TFI</span> Protein found in humans

COUP-TF1 also known as NR2F1 is a protein that in humans is encoded by the NR2F1 gene. This protein is a member of nuclear hormone receptor family of steroid hormone receptors.

<span class="mw-page-title-main">Thyroid hormone receptor alpha</span> Protein-coding gene in the species Homo sapiens

Thyroid hormone receptor alpha (TR-alpha) also known as nuclear receptor subfamily 1, group A, member 1 (NR1A1), is a nuclear receptor protein that in humans is encoded by the THRA gene.

<span class="mw-page-title-main">MED1</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the MED1 gene. MED1 functions as a nuclear receptor coactivator.

<span class="mw-page-title-main">NCOA6</span> Protein-coding gene in the species Homo sapiens

Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.

<span class="mw-page-title-main">SRA1</span> Protein-coding gene in the species Homo sapiens

Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein.

References

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