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editorial
. 2008 Aug 13;22(10):2213–2214. doi: 10.1210/me.2008-0201

Editorial: Coactivators and Corepressors: What’s in a Name?

Bert W O'Malley 1, Neil J McKenna 1
PMCID: PMC2582534  PMID: 18701638

Abstract

Nuclear receptor coregulators are molecules required for efficient function of nuclear receptors. The field of nuclear receptor coregulators has experienced remarkably rapid growth since its inception in the mid-1990s. With this growth has emerged a complex and often redundant nomenclature, which, although relatively familiar to those within the immediate field, has the potential to generate confusion as coactivators and corepressors come under increasing scrutiny in other, less familiar disciplines. We discuss this issue with reference to some specific examples and proffer some guidelines to the community for identifying these molecules.


THE FIELD OF nuclear receptor (NR) coregulators has experienced explosive growth over the past decade. There are now more than 300 of these important transcriptional regulatory molecules (see www.nursa.org for an exhaustive compilation), and they perform myriad functions in cells (1,2,3). Moreover, their importance to disease phenotypes is now unequivocal (4). With numerous publications dealing with coregulators, we have noted that the nomenclature is generating some confusion to scientists working peripheral to the main field. Many of the terms we have used for coregulators have familiar meanings with our immediate scientific colleagues, but as the technological and conceptual advances of the postgenomic era blur the edges of traditional scientific and clinical arenas, the need for less equivocal descriptors is becoming clearer. We illustrate this matter with reference to several specific issues.

Although correct in the broadest sense, use of the term “transcription factors” for coregulators is not sufficiently specific. At present, most scientists consider transcription factors primarily to refer to DNA-binding proteins such the NRs themselves. There are approximately 3000 such transcription factors, and their job is to seek out and bind to enhancers of genes and then to recruit the coregulators that carry out all subsequent enzymatic reactions required to activate or repress nuclear genes.

The term “cofactor” in reference to coregulators is in frequent use in the field. Indeed, when applied solely in the context of ancillary molecules for transcription factors, it might seem appropriate. However, this term has been in use for nearly 60 yr (5) in its most widely-understood context, namely a small inorganic or organic molecule required for full activity of many enzymes. With the growing appreciation of the importance of cellular enzymes in coregulator-mediated functions, the continued use of this term is likely to generate more confusion than it dispels. The discrepancy between the term “cofactor” being taken to refer to a small molecule by enzymologists, biochemists, and pharmacologists, and a protein up to 400 kDa when applied to NR coregulators, can be readily appreciated. This is less of a problem to specialist nuclear receptor and coregulator scientists within the field, but when the term is perpetuated in cross talk with overlapping disciplines, the potential for confusion increases.

It seems appropriate in the light of recent advances in the field to revisit some terms coined during the early development of the coregulator field. Molecules that provide activation potential for NRs have been traditionally called “coactivators,” and those that promote gene repression have been called “corepressors.” At the time these were selective, function-based descriptors, and their use has been constant since the discovery and initial characterization of these molecules. They often were assigned, however, based on the functional properties of these molecules in a single cell-based assay, the transient transfection reporter gene assay, which, although routine and expedient, lacked much of the functional and spatial context that is now understood to be of primary importance in determining the biological properties of these molecules. Subsequently, a number of laboratories showed that the functional directionalities of these molecules are not intrinsic (6,7,8,9,10). These apparent discrepancies are less bothersome to workers primarily in the field because they understand the reality and the mechanisms by which these different modes of action are acquired. For example, coactivators can be modified posttranslationally in select manners or bound to distinct proteins so as to cause a shift in their conformation that can then act to shut down genes instead of activating them. Similarly, corepressors can activate genes on some occasions. To convey these subtleties more clearly, the qualifier “selective coactivator” or “selective corepressor” could be applied in a specific biological context so as to help reinforce the notion that the properties that the molecule exhibits in that context might not necessarily translate to another.

Also, the field has generated a few more restrictive terms for members of the coregulator class. For example the term “p160 proteins” often is used by all of us to refer to the steroid receptor coactivator (SRC) family (SRC-1/-2/-3) of coactivators. Although generally descriptive, this term is also inadequate when placed in a wider biological context. It came into existence because these three family members run together in the same band of approximately 160 kDa on a protein electrophoretic gel. However, a number of other proteins and coactivators (e.g. proline-, glutamic acid-, and leucine-rich protein 1 (PELP1)/modulator of nongenomic action of estrogen receptor (MNAR), hSpt5, p160 rho kinase, and p160/myelin basic protein among others) are known to run in the same molecular mass band, and carry the same synonym, making the term open to equivocation. Disambiguation by the National Center for Biotechnology Information’s MEDLINE and Entrez Gene databases goes some way to clarifying the context in which these terms are used, but the onus is on us as scientists to avoid facilitating misunderstanding in the first place.

In the same vein, international standard reference names, when used in isolation, can provide another major level of confusion. Who among us is conversant with, or can even remember, those coregulators to which the names nuclear receptor coactivator (NCOA)4, NCOA5, or NCOA6 refer? Although these reference names have justifiable uses in high-throughput data processing and analysis, they may be the least useful of all terminologies for our everyday scientific conversation. The assignation of gene names by high-level organizations such as the Human Genome Nomenclature Committee, in our opinion, strays too far from familiarity in pursuit of a unique moniker for each ortholog of a specific molecule. Although multiple names are in themselves confusing, probably the best compromise is that individual laboratories continue to use their favorite specific term in conjunction with the appropriate, ortholog-specific official name. Under these guidelines, identification of members of the SRC coactivator family would be as follows: SRC-1/NCOA1; TIF2/NCOA2, GRIP1/Ncoa2, and SRC-2/Ncoa2; and AIB1/NCOA3, ACTR/NCOA3, pCIP/Ncoa3, RAC3/NCOA3, and SRC-3/Ncoa3.

In summary, the discoverers of molecules and functions traditionally have been allowed naming privileges throughout the history of science, and challenging this prerogative is a losing proposition. We propose, however, that the original/traditional name be coupled with the official name at least once in each article. In addition, we encourage the general use of the broader term “coregulator,” to afford an appreciation of the expanded functional compass of these molecules that recent studies have substantiated. Finally, it seems timely for us to begin applying the qualifier “selective coactivator/corepressor” in appropriate contexts. The journal level seems the most appropriate one for encouraging the adoption of these guidelines: the peer-review process exists to ensure the quality and accuracy of published articles, areas in which the objective of a more standardized, less ambiguous terminology for the field clearly lies.

Footnotes

This work was supported by Grant U19 DK062434 from the National Institute of Diabetes and Digestive and Kidney Diseases Nuclear Receptor Signaling Atlas.

Author Disclosure: The authors have nothing to disclose.

First Published Online August 13, 2008

Abbreviations: NCOA, Nuclear receptor coactivator; NR, nuclear receptor; SRC, steroid receptor coactivator.

References

  1. McKenna NJ, O'Malley BW 2002 Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465–474 [DOI] [PubMed] [Google Scholar]
  2. Hermanson O, Glass CK, Rosenfeld MG 2002 Nuclear receptor coregulators: multiple modes of modification. Trends Endocrinol Metab 13:55–60 [DOI] [PubMed] [Google Scholar]
  3. Lonard DM, O'Malley BW 2005 Expanding functional diversity of the coactivators. Trends Biochem Sci 30:126–132 [DOI] [PubMed] [Google Scholar]
  4. Lanz RB, Lonard DM, O'Malley BW 2008 Nuclear receptor coregulators in human diseases. In: Kumar R, O'Malley BW, eds. Nuclear receptor coregulators and human diseases. Singapore: World Scientific Publishing Co. Pte Ltd.; 1–135 [Google Scholar]
  5. Lichstein HC, Boyd RB 1952 A cofactor for the formic hydrogenylase enzyme system. Proc Soc Exp Biol Med 79:308–311 [DOI] [PubMed] [Google Scholar]
  6. Tagami T, Madison LD, Nagaya T, Jameson JL 1997 Nuclear receptor corepressors activate rather than suppress basal transcription of genes that are negatively regulated by thyroid hormone. Mol Cell Biol 17:2642–2648 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Rogatsky I, Zarember KA, Yamamoto KR 2001 Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J 20:6071–6083 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Weiss RE, Xu J, Ning G, Pohlenz J, O'Malley BW, Refetoff S 1999 Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J 18:1900–1904 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Peterson TJ, Karmakar S, Pace MC, Gao T, Smith CL 2007 The silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor is required for full estrogen receptor α transcriptional activity. Mol Cell Biol 27:5933–5948 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Yang Z, Hong SH, Privalsky ML 1999 Transcriptional anti-repression. Thyroid hormone receptor β-2 recruits SMRT corepressor but interferes with subsequent assembly of a functional corepressor complex. J Biol Chem 274:37131–37138 [DOI] [PMC free article] [PubMed] [Google Scholar]

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