Doi:10.1016/j.cell.2006.04.02

The Expanding Cosmos of Nuclear
Receptor Coactivators

David M. Lonard1 and Bert W. O'Malley1,*1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA*Contact: berto@bcm.tmc.edu DOI 10.1016/j.cell.2006.04.021 About 200 coactivators play a central role in promoting gene expression mediated by nuclear receptors. This diverse group of proteins are key integrators of signals from steroid hormones and have been implicated in cancer and other diseases.
associated proteins such as histone coactivator's final agenda—that is, to Nuclear receptors (NRs) comprise a deacetylases enforce a local chro- see a particular gene expressed as a superfamily of conserved transcrip- matin environment that opposes the mature functional protein.
tion factors that are activated by their transcription-promoting activities of After identification of the first steroid hormone ligands and play coactivators (such as histone acetyl- NR coactivator—the steroid recep- essential roles in diverse biological transferase). Through their opposing tor coactivator SRC-1 (Onate et al., processes. For example, the estro- actions, a balance exists between 1995)—it was predicted that there gen, progesterone, and androgen coactivators and corepressors that might be a small family of coactiva- receptors are important in reproduc- defines the magnitude and nature of tors (perhaps five to ten) that carried tion; glucocorticoid receptors in glu- responses to NR ligands.
out the bridging role between tran- cose metabolism and stress; the thy- scription factor and transcriptional roid hormone receptor in oxidative Coactivators and Transcriptional
machinery. There are now ?200 pub- metabolism; and PPARs in lipid and lished NR coactivators that work with energy metabolism (Mangelsdorf et Initial experiments in yeast pro- ?48 NRs. Of these, ?50–70 have al., 1995). Coactivators are molecules duced a picture of coactivators as been characterized by more than recruited by ligand bound activated "transcriptional adaptors" (Ptashne one laboratory and have been defini- NRs (or other DNA binding transcrip- and Gann, 1990). These adaptors tively shown to be NR coactivators. tion factors) that elicit enhanced were predicted to provide a bridge Clearly, we are far from identifying gene expression. In contrast to NRs, between DNA binding transcription the totality of authentic NR coactiva- which are structural y conserved, factors and the general transcription tors (http://www.nursa.org) or their their coactivators are diverse, both machinery. This simple scenario of specific functions in the cel .
structural y and in the way they con- coactivator action turned out to be Transcription is a highly dynamic tribute to the transcriptional process, much more complex.
and orderly process involving many namely through a diverse array of Coactivators are predicted to have subreactions (multiple steps of ini- enzymatic activities such as acety- many activities in addition to the tiation, elongation, splicing, and ter- lation, methylation, ubiquitination, initiation of transcription, such as mination). Given that so many NR and phosphorylation or as chroma- mRNA transport from the nucleus, coactivators have been identified, tin remodelers. NR coactivators are mRNA translation, and posttransla- there is certainly no shortage of them essential effectors of the biological tional modifications of the synthe- to participate in the wide variety of activities of NRs and their ligands sized protein. That coactivators pos- transcription subreactions. But why (Xu et al., 1999). Although the focus sess stratified actions in the entire would a cell possess such a cumber- of this essay is NR coactivators, con- process of transcription/translation some transcriptional apparatus? The ceptual y they work in a manner simi- reflects the fact that they do not act answer may lie in the fact that mam- lar to general coactivators for other alone but rather as part of multipro- mals are substantial y more complex tein complexes. These multisubunit than organisms such as yeast, worm, There is little doubt that the coun- entities, containing many individual and the fruit fly, which have far fewer terparts of coactivators, corepres- enzymatic activities, represent a NR coactivators. For instance, only sors, are equal y important to the complex machine that is able to con- a single NR coactivator (Taiman/ cell (Glass and Rosenfeld, 2000). centrate and link diverse enzymes, dAIB1) has been identified in fruit Corepressors interact with NRs and the processes that they regulate, flies so far.
that are not bound to ligand and together in one place. In this way, the Coactivator activity results in par- repress transcription. Corepressor- coactivator complex executes the ticular physiological consequences. Cell 125, May 5, 2006 2006 Elsevier Inc. 411


degradation system PGC-1 coactivator is plays a positive role expressed when an in transcription prior organism needs to to a subsequent duty alter its metabolic pro- in transcription ter- gram in response to mination (Reid et al., exercise or cold tem- 2003). This theory peratures (Lin et al., 2005). Work in mice the large number of lacking the coactiva- coactivators that are tors SRC-1 and SRC- E2 and E3 ligases, 2 reveals their impor- such as E6-AP, RPF- tance in carbohydrate 1, UbcH7, and p300. and lipid metabolism One can envisage (Picard et al., 2002). the recruitment of a Thus, although at first procession of coacti- glance they appear to vators—for example, act only in transcrip- during transcription tional control, coacti- initiation, there would vators are impor- be SRCs and p68; tant for modulating chromatin remodel- the expression of a ers such as BRG-1 wide array of physi- and other ATPase- ological y important dependent chroma- groups of genes.
tin remodelers; and histone A Cacophony of
(histone acetyltrans- Figure 1. Coactivator-Directed Gene Expression
(Left panel) Activation of a nuclear receptor (NR) by binding of its steroid-hormone ferases and methyl- For transcription to ligand results in activation of kinase A, which induces a distinct phosphorylation proceed, there need to pattern (P) in a core coactivator (Core CoA). Protein remodelers (Pin1, Hsps, pro- as p300/CBP, SRCs, teasome ATPases) direct the incorporation of a unique set of co-coactivators (Co be histone modifica- Co; examples include p300 and the ubiquitin-conjugating ligases UbC and UbL) and CARM-1. Later tions (such as acetyla- into a distinct multiprotein coactivator complex. The composition of this com- during transcription, tion and methylation), plex favors enhancement of NR-mediated transcription of target genes. Various elongation would be ATPase-dependent enzymatic activities assigned to these co-coactivators (acetylation, Ac; methyla- mediated by P-TEFb tion, Me) can target protein members of neighboring complexes. This results in chromatin remodeling, dissociation of members of these complexes, followed by their destruction by fol owed by alterna- initiation of transcrip- tive splicing of mRNA tion, elongation, alter- (Right panel) Signaling through membrane receptors via kinase B induces a phos- by PGC-1, CAPER, phorylation pattern distinct from that of Core CoA. This pattern results in the in- native RNA splicing tegration of alternative co-coactivators (Co Co), leading to a complex that favors and CoAA. Final y, and mRNA process- transcription mediated by non-NR transcription factors (TF). After their transcrip- ing, and termination. tional roles are complete, the complexes are ubiquitinated and degraded by the plex remodeling or The focus of coactiva- the termination of its tor enzymatic activi- activities would be ties in these processes accomplished by E6- has centered on the posttranslational For cessation of transcription, RNA AP, SSA, and TRIP1 (Metivier et al., modification of histones and chroma- polymerase must dissociate from the 2006). There is no doubt that newly tin. However, it is becoming clear gene and reinitiation of transcrip- identified coactivators will continue that NRs and their coactivators are tion must be curtailed. As part of the to be a prime source for the discov- also subject to posttranslational cessation of transcription, coactiva- ery of new molecular events in tran- modification. For instance, ligand- tors and their NRs are modified by dependent sumoylation of PPARγ ubiquitination and degraded by the mediates the repression of inflam- proteasome. In addition to transcrip- Coactivators: Integrators of the
matory response genes (Pascual tional termination, the ubiquitin pro- et al., 2005). The posttranslational teasome degradation system is likely Primary or core coactivators—those targeting of NRs and their coacti- to be important in clearing "used" that interact directly with NRs—exist vators is important because these coactivator complexes from the pro- in steady-state complexes with sec- modifications influence the expres- moter, al owing for subsequent steps ondary or co-coactivator partners sion of functionally related groups in sequential transcription to ensue. (Stal cup et al., 2003) (see Figure Here, the ubiquitin proteasome 1). The coactivator core complex is 412 Cell 125, May 5, 2006 2006 Elsevier Inc.
composed of a tightly bound invari- final occupation of binding sites on Transcriptional Dynamics:
ant group of proteins, whereas the protein partners is a product of both Remodeling, Removal, Reinitiation
more loosely bound co-coactivators their cel ular concentration and their That many coactivators contribute associate with the core complex in affinity for each other. In the case of to NR-dependent gene expres- a dynamic, regulated manner. Per- SRC-3, phosphorylation of a spe- sion suggests the presence of a haps a higher-order "complex of cific combination of residues defines dynamic force that acts as a pro- complexes" also forms, enabling which transcription factors this coact- pulsion system for these transcrip- coactivator intercomplex commu- ivator is able to activate, suggesting tional machines. In a simple system nication and efficient integration of that there may be a "phosphorylation involving only a few proteins, thermal signaling pathways such as those code" (Wu et al., 2005). The selec- Brownian-driven association and required for metabolism, growth, tively phosphorylated coactivator dissociation would be sufficient to and inflammation. The fact that can be conscripted to preferential y al ow for the necessary proteins to coactivators belong to distinct com- implement the expression of genes associate, perform their enzymatic plexes may explain how more than downstream of a particular growth- roles, and dissociate, al owing other 200 different coactivator proteins factor signaling cascade. Binding of proteins to then be recruited to do individually contribute to cell regula- coactivators to NRs general y occurs their jobs. Although Brownian forces tion in a coherent manner.
through LXXLL interaction motifs in are likely to play some role, such a Because coactivators exist as mul- the coactivator. Many coactivators simple physical force is unlikely to be tiprotein complexes, a member of a possess several different receptor- sufficient for transcription to ensue. single coactivator complex can serve interacting LXXLL motifs, enabling An orderly procession of coactiva- as a rate-limiting conduit to control them to bind to different combina- tor proteins must associate with the the actions of the whole complex. tions of NRs. Complexity is also promoter for efficient transcription For example, the phosphorylation afforded through these LXXLL motifs (An et al., 2004). Many other pro- status of SRC-3 defines its associa- by amino acid residues that flank teins interact with the promoter in an tion with other members of the com- these sequences. In some cases, orderly sequential fashion (Reid et plex, such as p300 and CBP histone these flanking residues are also sub- al., 2003), such that additional orga- acetyltransferase or CARM1 meth- ject to posttranslational modifica- nizing processes must be involved to yltransferase (Wu et al., 2005). This tions, al owing for the dynamic con- actively disrupt and rearrange these attendant signaling feature afforded trol of this NR-interacting motif.
by coactivator complexes suggests So what are some of the motive that coactivators may be integrators Histone Modification: Directed
forces that al ow for orderly remod- of multiple cell signaling systems. versus Distributed Regulation
eling capabilities? Protein degrada- Activation of membrane receptors Coactivator-mediated histone modi- tion via the proteasome is one force and signaling cascades may al ow fications play an important role in that makes this procession possible. the genome to sense the impact of regulating the transcription of a par- Because protein degradation medi- the total environment on the cel . ticular gene, but the biological impact ated by the ubiquitin-proteasome Given that coactivators can organize is limited usual y to that target gene. system is a highly regulated and spe- the expression of "functional groups" Coactivators, however, can direct cific process, it is capable of selec- of genes involved in the execution of their enzymatic action toward other tively removing coactivator proteins a specific regulatory regime (such coactivator proteins (Xu et al., 2003; after they have fulfil ed their roles in as genes involved in metabolism, Lee et al., 2005). Conceptual y, cross- transcription, clearing the way for growth, or cytokine action), they are posttranslational modification of one subsequent coactivator associations prime targets for posttranslational coactivator by another would al ow the with the promoter. The ubiquitin-pro- modification and modulation by affected coactivator (and the coacti- teasome system is itself remarkably kinase cascades (Wu et al., 2005). vator complex that it resides in) to complex, as evidenced by the large Phosphorylation of coactivators by act in an altered manner on a "global number of ubiquitin ligases responsi- kinases, such as IKKα and CDK2, scale" similar to the far-reaching bio- ble for the directed targeting of ubiq- modulates NR-mediated transcrip- logical effects that kinases exert on uitin to proteasome substrates, mak- tion by altering the affinity between SRC-3 function. Although the histone ing it the largest class of enzymes different coactivators and their NRs, modification code may define the tran- in mammalian cel s. Another group influencing which transcription fac- scriptional state of individual genes, of proteins that may play essential tors they are able to coactivate (Wu coactivator modification codes (acety- roles in coactivator dynamics are et al., 2005; Narayanan et al., 2005). lation, methylation, phosphorylation) the ATP-driven protein chaperones. Other modifications, such as methyl- may define the transcriptional state of An example of a protein that alters ation or acetylation, can promote the broad groups of functional y related coactivator protein conformation is dynamic dissociation of coactiva- genes and may control coactivator Pin1, a prolyl isomerase that cata- tor-complex components (Xu et al., preferences among NRs and other lyzes the cis-trans isomerization of 2003; Lee et al., 2005). In the end, transcription factors (see Figure 1).
proline residues in SRC-3 (see Fig- Cell 125, May 5, 2006 2006 Elsevier Inc. 413 ure 1). Such a transition in a proline through transcription of their parent Lanz, R.B., McKenna, N.J., Onate, S.A., Al- residue is capable of evoking a large genes, then those genes also would brecht, U., Wong, J., Tsai, S.Y., Tsai, M.-J., and O'Malley, B.W. (1999). Cell 97, 17–27.
steric change in the protein and can require their own set of regulatory serve as an additional mechanism coactivators and so on, resulting in Lee, Y.H., Coonrad, S.A., Kraus, W.L., Jelinek, to dynamical y alter coactivator pro- a never-ending circle of regulatory M.A., and Stallcup, M.R. (2005). Proc. Natl. Acad. Sci. USA 102, 3611–3616.
tein conformation during complex Coactivators play important roles in Lin, J., Handschin, C., and Spiegelman, B.M. (2005). Cell Metab. 1, 361–370.
diverse pathological processes, such RNA Coactivator Complexes
as cancer, inherited genetic diseases, Mangelsdorf, D.J., Thummel, C., Beato, M., SRA is a unique NR coactivator in metabolic disorders, and inflam- Herrlich, P., Schutz, G., Umesono, K., Blum-berg, B., Kastner, P., Mark, M., Chambon, P., that it is an RNA (Lanz et al., 1999). mation. The cancer cel , dedicated and Evans, R.M. (1995). Cell 83, 835–839.
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by pseudouridine synthase (which E6-AP result in the inherited genetic converts uracil to pseudouracil) that Narayanan, R., Adigun, A.A., Edwards, D.P., disease Angelman syndrome, (Mat- and Weigel, N.L. (2005). Mol. Cell. Biol. 25, alters its conformation (Zhao et al., suura et al., 1997). Polymorphisms 2004). RNAs may be an important in PGC-1 may lead to increased sus- structural molecule in coactivator Onate, S.A., Tsai, S.Y., Tsai, M.-J., and ceptibility to type II diabetes (Lin et O'Malley, B.W. (1995). Science 270, 1354– complexes, playing a part similar to al., 2005). Final y, variations in the that of structural RNAs in ribosomes. expression of coactivators among dif- Pascual, G., Fong, A.L., Ogawa, S., Gamliel, A number of splicing-related coacti- ferent individuals may be associated A., Li, A.C., Perissi, V., Rose, D.W., Wilson, vators such as p68, p72, CAPER, and with phenotypic differences among T.M., Rosenfeld, M.G., and Glass, C.K. (2005). PGC-1 possess RNA binding motifs; Nature 437, 759–763.
humans. There is little doubt that we their uncharacterized RNA binding have much to learn about the biologi- Picard, F., Gehin, M., Annicotte, J., Rocchi, S., partners may represent other RNA cal y diverse roles of NR coactivators Champy, M.F., O'Malley, B.W., Chambon, P., coactivators. SRA is also a part- and Auwerx, J. (2002). Cell 111, 931–941.
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This work was supported by NIH grants to B.W.O. (HD 08818 and 07857) and NIDDK- Stallcup, M.R., Kim, J.H., Teyssier, C., Lee, If coactivators are key regulators of Y.H., Ma, H., and Chen, D. (2003). J. Steroid transcription, what regulates their Biochem. Mol. Biol. 85, 139–145.
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Zhao, X., Patton, J.R., Davis, S.L., Florence, scription of the parent gene. If regu- Glass, C.K., and Rosenfeld, M.G. (2000). B., Ames, S.J., and Spanjaard, R.A. (2004). lation of coactivators occurred only Genes Dev. 14, 121–141.
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414 Cell 125, May 5, 2006 2006 Elsevier Inc.

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