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Minireview: Nuclear Receptor Coactivators—An Update

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Bert W. O’Malley, M.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: . berto{at}bcm.tmc.edu

	Abstract

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Nuclear receptors (NRs) regulate the expression of target genes in response to activation by steroid hormones and other ligands, as well as a variety of other signaling pathways. NR coactivators are defined as cellular factors recruited by activated NRs that complement their function as mediators of the cellular response to endocrine signals. In this review, we will focus upon advances in our understanding of the function of coactivators as their characterization has progressed from mechanistic studies to an exploration of their biological roles in living animals.

	Introduction

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NUCLEAR RECEPTORS (NRs) are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. The biological effects of these ligands are manifest in processes ranging from organogenesis during development, to regulation of metabolic pathways, to stimulating proliferation in reproductive tissues. Approximately 50 NRs are known to exist, and together, these proteins comprise one of the largest families of metazoan transcription factors, the NR superfamily, whose structure is defined by a number of signature functional domains (1, 2, 3). Generally, NRs are comprised of: an amino-terminal activation function, activation function (AF)-1 (A/B domain); the DNA-binding domain; a hinge region; and a carboxy-terminal ligand-binding domain containing a second activation function, AF-2.

NR coregulators can be broadly defined as cellular factors recruited by NRs that complement their function as mediators of the cellular response to endocrine signals. They are generally divisible into coregulators that promote transcriptional activation when recruited (coactivators), and those that attenuate promoter activity (corepressors). A discussion of the role of corepressors in NR function is beyond the scope of this minireview, and the reader is referred to recent reviews for thorough coverage of this topic (4, 5). We will highlight advances in our understanding of the function of coactivators as their characterization has progressed from in vitro studies to an evaluation of their biological significance in living animals.

A large number of coactivators are known to exist, and over recent years, their study has been firmly established as a research field in its own right. While progress has been made toward elucidating their functions at promoters, the issues of the physiological and metabolic roles of coactivators, their tissue distribution, and their contribution to functional diversity of NR action in vivo, remain largely unresolved. A recurring question in the field is the molecular basis for the number of individual coactivators, and the extent to which receptors and coactivators effect differential spatiotemporal responses to ligands at the organism, tissue and gene levels.

	In Vitro Characterization of Coactivators: A Molecular Model

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Progress to date in characterizing the function of coactivators on a mechanistic level has constructed a composite model of their role in NR action (Fig. 1). Initial contact between activated NRs and coactivators is believed to be mediated in large part by an amphipathic helix conserved on the surface of most coactivators, the LXXLL motif, or NR box (6). Crystallographic evidence has shown that a ligand-dependent shift in the position of several critical helices in AF-2 of the receptor ligand binding domain, notably helix 12, creates a thermodynamically secure environment for the coactivator NR box (7). This relatively localized union between receptor and coregulator suggests that it may hold considerable potential for peptide-based therapeutic manipulation of NR pharmacology, and as a flexible, informative basis for ligand screening assays (8).

View larger version (17K): [in this window] [in a new window]   Figure 1. General model of coactivator function in transcriptional regulation by nuclear receptors. See text for details. Hi, Histones. Due to space and reference limitations we are unable to cite references for individual coactivators, and instead refer the reader to more in-depth recent reviews (4 5 ).

	Chromatin—Remodeling Factors

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	Acetyltransferases

Top Abstract Introduction In Vitro Characterization of... Chromatin—Remodeling... Acetyltransferases Contact with General... Regulating Coactivators:... Receptor and Ligand-Specific... What Are the Biological... Considerations for the Future References

 
While ATPase complexes are thought to largely effect noncovalent disruption of large chromatin domains, local regulation of histone-histone and histone-DNA interactions are mediated in part by members of a family of proteins that were among the first to be identified as NR coactivators, the steroid receptor coactivator (SRC)/p160 family. Members of the SRC family [SRC-1/nuclear coactivator-1 (10, 11); glucocorticoid receptor-interacting protein-1/TIF2/SRC-2 (12, 13); and p300/cAMP response element binding protein (CREB)-binding protein-interacting protein/activator of thyroid receptor/amplified in breast cancer-1/receptor-associated coactivator-3/thyroid receptor-associated molecule-1/SRC-3 (14, 15, 16, 17, 18, 19)] contain a number of shared domains, including a central region containing repeating NR boxes.

The structural homology between SRC family members is reflected in their overlapping functional properties, such as acetyltransferase activity. Histones are thought to maintain a repressive transcriptional environment at the promoter through electrostatic contacts between positively charged lysine side chains and negatively charged DNA phosphate groups. By catalyzing the acetylation of histone lysines, SRC family members and other histone acetyltransferases such as CREB-binding protein (CBP) and p300 (see below) are thought to disrupt the interactions responsible for maintaining the promoter region in a "closed" state. Of the SRC family members, SRC-1 and ACTR/SRC-3 have been shown to possess intrinsic acetyltransferase activity (15, 20)

The physiological role of SRC/p160s as coactivators has been implied by knockout studies of genes encoding these proteins (21, 22, 23). Although the phenotypes of these knockouts are largely subtle in nature, they do provide some clues as to their functions, and to significant differences between SRC/p160 family members. SRC-1 knockout mice show a partial resistance to hormones and a reduced growth and development of various steroid target organs. SRC-3 knockout mice show reduced growth and female reproduction, and lack of mammary gland development. In addition, mouse embryonic fibroblasts or liver cells derived from these SRC-3^-/- mice are insensitive to growth stimulation by IGF-1 or GH. The participation of SRC-3 in cell growth is further supported by its role in various cancers—it has been demonstrated that the SRC-3 gene is amplified in 5–10% of breast tumors and 7–8% of ovarian cancer samples (19).

Along with the SRC family, another well characterized NR coactivator is CBP and its closely related factor, p300, which have been shown to complement the activities of many transcription factors, including p53 and NRs (24, 25). Like the SRC/p160 family members SRC-1 and ACTR/SRC-3. CBP and p300 contain intrinsic acetyltransferase activity and appear to be the predominant acetyltransferases for histones. Unlike SRC/p160 family members, however, heterozygous and null mutants of CBP and p300 exhibit dosage-dependent pleiotropic defects in a variety of morphogenetic and cell differentiation processes, indicating their importance in early mammalian development (26, 27). This apparent partitioning of coactivator function in different developmental stages is one possible clue to the profusion of coactivators that exists to mediate NR function.

	Contact with General Transcription Factors

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A third prominent group of coactivators is represented by thyroid receptor-associated proteins (TRAP)/vitamin D receptor-interacting proteins (DRIP), a complex initially identified in separate biochemical screens for proteins recruited by thyroid hormone receptor (28) and vitamin D receptor (29), respectively. Subsequent studies have shown TRAP/DRIP to be capable of enhancing the function of other receptor types, and this has been interpreted as evidence of a general role of the complex in NR-mediated signaling. Molecular studies indicate that the complex may play a role in directly contacting the basal transcriptional machinery. Consistent with such a pivotal role in NR-mediated transcriptional regulation, null mutation of the gene encoding a NR box-containing TRAP/DRIP subunit (TRAP220) results in embryonic lethality attributable to a variety of pleiotropic abnormalities (30), including defects in cell cycle regulation and increased apoptosis.

	Regulating Coactivators: Posttranslational Modification

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How are the functional properties of a given number of coactivators partitioned to account for their ability to integrate NR function at a wide variety of promoters with a broad spectrum of cellular signals? To pose the question another way, how might coactivators be addressed to mediate the specific spatiotemporal fingerprint for given genes or gene sets? One school of thought suggests that posttranslational modifications such as acetylation or phosphorylation may have a role in specifying the codes that tune a given coactivator to a specific mechanistic role. One of the first studies to highlight their potent influence upon the molecular choreography of NRs and their coregulators at specific promoters was the demonstration of p300-mediated acetylation of lysine residues in the vicinity of the ACTR/SRC-3 NR boxes that resulted in the uncoupling of the interaction between the estrogen receptor (ER) and ACTR on pS2, cathepsin D, and c-myc promoters (31). More recently, chromatin immunoprecipitation analysis of the p21 promoter has shown that mutation of the p53 target acetylation region prevented its recruitment of coactivator complexes, including CBP (32). These studies are reminiscent of earlier studies describing promoter-specific functions of individual coactivators, and highlight the importance of promoter and transcription factor context in determining the functional consequences of posttranslational modification.

Phosphorylation, which has been historically implicated in NR function (33), is currently emerging as a critical posttranslational modification in the context of coactivators, and its effect takes a variety of forms. Knutti et al. (34) have shown that p38 MAPK-mediated phosphorylation of peroxisomal proliferator-activated receptor--coactivator-1 results in reversal of its sequestration in a nonfunctional complex by a repressor. In a further example of the context dependency of posttranslational modification, phosphorylation of amplified in breast cancer-1/SRC-3 by MAPK increases the half life of its association with p300 (35). Moreover, phosphorylation has been shown to enhance acetyltransferase activity, and can function as a determinant of the subcellular localization of coactivators (for a review, see Refs. 4 and 5). These studies and others present a molecular basis for the well-characterized functional cross talk between NRs and growth factors to which many endocrinological studies have pointed. Taken together, they suggest that to us that transcription factor-specific, coactivator-specific, and promoter-customized sequences of posttranslational modification may contribute to the amplitude, timing and duration of transcription of individual genes.

To summarize, in vitro molecular approaches have constructed a sequential model of coactivator action that envisages recruitment by receptor of chromatin modifying factors, followed by histone and factor acetyltransferase activity, with TRAP/DRIP-like complexes ultimately contacting basal transcription factors (Fig. 1). Recent studies have hinted at a role for coactivators in influencing events downstream of transcriptional initiation (36, 37), although the precise nature of these roles is as yet unclear. Orchestrating the recruitment and participation of individual factors in this sequence of events is a series of posttranslational modifications, which might occur in a promoter-specific context. Given this basic model, scenarios can be envisaged that might require adaptation of this basic framework. For example, the model assumes the existence of a restrictive chromatin milieu requiring recruitment of an initial battery of chromatin-modifying coregulators to facilitate access of secondary TRAP/DRIP-like coregulator complexes to the promoter. What series of events might account for NR regulation of a promoter that is already active in response to signaling by another, distinct signaling axis? Intuitively, a permissive chromatin environment might be less likely to require the incorporation of chromatin modifying complexes or histone acetyltransferases activities by the receptor.

	Receptor and Ligand-Specific Coactivator Recruitment

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The selective recruitment of coactivators by individual receptors has been well established (38, 39). Moreover, the intricate spatiotemporal pharmacology of NR ligands and their synthetic derivatives, the selective receptor modulators, may be attributable in part to their ability to specify the identity of coactivators recruited by individual receptors. Vitamin D receptor, for example, has been reported to discriminate between SRC-1 and TIF2/SRC-2 to different degrees depending upon the ligand to which it is bound (40). Moreover, distinct ER and ERß ligands are known to effect preferential recruitment of different coactivators (41, 42). The attribution of such effects to ligand-specific manipulation of receptor tertiary structure is supported by crystallographic studies of ER bound to different selective ER modulators; see Ref. 7). Moreover, in the case of peroxisomal proliferator-activated receptor-, the synthetic antidiabetic roziglitazone effects selective recruitment of TIF2, whereas a leucine-containing peptide induces an allosterically unique conformation, and is associated with a distinct peroxisomal proliferator-activated receptor pharmacology and target gene induction specificity (43). Selective receptor/coactivator interactions represent an efficient system through which the pleiotropic effects of NR ligands might be mediated, and are likely further determined by tissue-specific patterns of posttranslational modification of coactivators (44).

	What Are the Biological Roles of Coactivators?

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There is a limit to the complexity of coactivator function that the essentially composite model of NR and coactivator action we have discussed (Fig. 1) is capable of conveying. As alluded to above, emerging evidence suggests that coactivator function is a highly contextual chain of events, pointing to what is likely a rich and complex biology for these factors. While null deletions have indicated that several coactivators (CBP, p300, TRAP/DRIP) are essential for viability, these are likely to be the exception, and the majority of these factors will likely require more subtle approaches to defining their biological roles. While we have cited promoter context as an important variable, a variety of studies have highlighted receptor and ligand identity and tissue specificity as other principal determinants of coactivator function.

Recent in vivo studies have highlighted important distinctions between individual groups of coactivators for which their initial molecular characterization did not initially account. Evidence is emerging that specific coactivator fingerprints may determine the spatiotemporal response of individual tissues to distinct hormones. For example, the androgen receptor, ER, and progesterone receptor coactivator E6-associated protein (AP) is expressed in both the virgin mammary gland and the prostate. Studies of the E6-AP null mutant indicate, however, that it is redundant for estrogen and progesterone-induced mammary gland growth while required for proper testosterone-mediated prostate gland growth (45). These results stand in contrast to the impaired mammary gland development characteristic of the SRC-1 and SRC-3 null mutants. In turn, in contrast to the tissue-specific phenotypes of E6-AP and SRC-1/3 null mutant animals, the severe developmental phenotypes resulting from deletion of PBP/TRAP220, CBP, and p300 are consistent with their evolutionary conservation, and their mediation of a very broad range of cellular signals. Their in vivo characterization suggests they may play a role in integrating multiple cellular stimuli at critical transcriptional loci during fundamental developmental processes.

	Considerations for the Future

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Initial mechanistic approaches that invested coactivators with an amplificatory role at NR-regulated promoters were predicated upon an enhancement of NR function in transient transfection and, more recently, in in vitro transcription assays. These observations were made in the context of cultured cells containing supraphysiological levels of coactivator, receptor and synthetic template. Such assays, which vary with respect to cell type, DNA amounts, vector and reporter type, and promoter activity assay method, do not readily lend themselves to comparative quantitative analysis. While they and other assays have been of great value in the functional characterization of coactivators, they afford only the most tenuous biological extrapolation. There is little reason to suppose that native promoters in vivo would support the levels of amplification observed in transient transfection. Indeed, in vivo demonstrations of ligand response in wild-type and coactivator null mutant mice point to a role for coactivators in a rather more complex regulatory scenario.

One of the principal issues confronting the field is the need to reconcile the wealth of in vitro observations with a complete in vivo picture of coactivator biology. A firmer grounding in the cellular physiology of coactivators should greatly aid investigators seeking to explore the pathological ramifications of coactivator mis-expression or mutation. The strides taken toward characterizing the mechanistic complexities of many coactivators gives hope for the future, and we anticipate many intriguing twists as the biology of coactivators unfolds in the near future.

	Acknowledgments

 
We thank Drs. Austin Cooney, Fred Pereira, and Zafar Nawaz for helpful comments.

	Footnotes

 
Work leading to the conclusions summarized herein was supported by the National Institute of Child Health and Human Development and the National Institute of Diabetes, Digestive and Kidney Diseases. N.J.McK. is a recipient of a Department of Defense Breast Cancer Postdoctoral Research Fellowship.

Abbreviations: AF, Activation function; ATPase, adenosine 5'-triphosphatase; CBP, CREB binding protein; CREB, cAMP response element binding protein; DRIP, vitamin D receptor-interacting proteins; E6-AP, E6-associated protein; ER, estrogen receptor; NR, nuclear receptor; SET, Su(var)3-9/enhancer of zeste/trithorax; SRC, steroid receptor coactivator; TIF1, transcription intermediary factor-; TRAP, thyroid receptor-associated proteins.

Received December 13, 2001.

Accepted for publication March 13, 2002.

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				H. J. Li, Z. Haque, Q. Lu, L. Li, R. Karas, and M. Mendelsohn Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation PNAS, March 6, 2007; 104(10): 4065 - 4070. [Abstract] [Full Text] [PDF]

				S. Cascio, V. Bartella, C. Garofalo, A. Russo, A. Giordano, and E. Surmacz Insulin-like Growth Factor 1 Differentially Regulates Estrogen Receptor-dependent Transcription at Estrogen Response Element and AP-1 Sites in Breast Cancer Cells J. Biol. Chem., February 9, 2007; 282(6): 3498 - 3506. [Abstract] [Full Text] [PDF]

				A. Romano, B. Delvoux, D.-C. Fischer, and P. Groothuis The PROGINS polymorphism of the human progesterone receptor diminishes the response to progesterone J. Mol. Endocrinol., February 1, 2007; 38(2): 331 - 350. [Abstract] [Full Text] [PDF]

				H.-G. Yoon and J. Wong The Corepressors Silencing Mediator of Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Are Involved in Agonist- and Antagonist-Regulated Transcription by Androgen Receptor Mol. Endocrinol., May 1, 2006; 20(5): 1048 - 1060. [Abstract] [Full Text] [PDF]

				K.-H. Song, T. Li, and J. Y. L. Chiang A Prospero-related Homeodomain Protein Is a Novel Co-regulator of Hepatocyte Nuclear Factor 4{alpha} That Regulates the Cholesterol 7{alpha}-Hydroxylase Gene J. Biol. Chem., April 14, 2006; 281(15): 10081 - 10088. [Abstract] [Full Text] [PDF]

				D. P. Simmons, M. L. Peach, J. R. Friedman, M. M.B. Green, M. C. Nicklaus, and L. M. De Luca Evidence that sequence homologous region in LRAT-like proteins possesses anti-proliferative activity and DNA binding properties: translational implications and mechanism of action Carcinogenesis, April 1, 2006; 27(4): 693 - 707. [Abstract] [Full Text] [PDF]

				Y. Ogura, M. Azuma, Y. Tsuboi, Y. Kabe, Y. Yamaguchi, T. Wada, H. Watanabe, and H. Handa TFII-I down-regulates a subset of estrogen-responsive genes through its interaction with an initiator element and estrogen receptor {alpha} Genes Cells, April 1, 2006; 11(4): 373 - 381. [Abstract] [Full Text] [PDF]

				D. A. Proia, B. W. Nannenga, L. A. Donehower, and N. L. Weigel Dual Roles for the Phosphatase PPM1D in Regulating Progesterone Receptor Function J. Biol. Chem., March 17, 2006; 281(11): 7089 - 7101. [Abstract] [Full Text] [PDF]

				O. Y. Khan, G. Fu, A. Ismail, S. Srinivasan, X. Cao, Y. Tu, S. Lu, and Z. Nawaz Multifunction Steroid Receptor Coactivator, E6-Associated Protein, Is Involved in Development of the Prostate Gland Mol. Endocrinol., March 1, 2006; 20(3): 544 - 559. [Abstract] [Full Text] [PDF]

				S. Jiang, R. Meyer, K. Kang, C. K. Osborne, J. Wong, and S. Oesterreich Scaffold Attachment Factor SAFB1 Suppresses Estrogen Receptor {alpha}-Mediated Transcription in Part via Interaction with Nuclear Receptor Corepressor Mol. Endocrinol., February 1, 2006; 20(2): 311 - 320. [Abstract] [Full Text] [PDF]

				D. R. Buchholz, B. D. Paul, and Y.-B. Shi Gene-specific Changes in Promoter Occupancy by Thyroid Hormone Receptor during Frog Metamorphosis: IMPLICATIONS FOR DEVELOPMENTAL GENE REGULATION J. Biol. Chem., December 16, 2005; 280(50): 41222 - 41228. [Abstract] [Full Text] [PDF]

				R. Safi, A. Kovacic, S. Gaillard, Y. Murata, E. R. Simpson, D. P. McDonnell, and C. D. Clyne Coactivation of Liver Receptor Homologue-1 by Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha} on Aromatase Promoter II and Its Inhibition by Activated Retinoid X Receptor Suggest a Novel Target for Breast-Specific Antiestrogen Therapy Cancer Res., December 15, 2005; 65(24): 11762 - 11770. [Abstract] [Full Text] [PDF]

				D. J. Mulholland, S. Dedhar, G. A. Coetzee, and C. C. Nelson Interaction of Nuclear Receptors with the Wnt/{beta}-Catenin/Tcf Signaling Axis: Wnt You Like to Know? Endocr. Rev., December 1, 2005; 26(7): 898 - 915. [Abstract] [Full Text] [PDF]

				Z. Zhang, A. M. Olland, Y. Zhu, J. Cohen, T. Berrodin, S. Chippari, C. Appavu, S. Li, J. Wilhem, R. Chopra, et al. Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget J. Biol. Chem., August 5, 2005; 280(31): 28468 - 28475. [Abstract] [Full Text] [PDF]

				K D S. A. Wansa and G. E O Muscat TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors J. Mol. Endocrinol., June 1, 2005; 34(3): 835 - 848. [Abstract] [Full Text] [PDF]

				P. Chambon The Nuclear Receptor Superfamily: A Personal Retrospect on the First Two Decades Mol. Endocrinol., June 1, 2005; 19(6): 1418 - 1428. [Full Text] [PDF]

				T. Ishizuka and M. A. Lazar The Nuclear Receptor Corepressor Deacetylase Activating Domain Is Essential for Repression by Thyroid Hormone Receptor Mol. Endocrinol., June 1, 2005; 19(6): 1443 - 1451. [Abstract] [Full Text] [PDF]