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15 Smith, R.G. et al. (1999) A new orphan receptor involved in pulsatile growth hormone release. Trends Endocrinol. Metab. 10, 128–135 16 Guan, X.M. et al. (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. Mol. Brain Res. 48, 23–29 17 Meunier, J.C. et al. (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535 18 Reinscheid, R.K. et al. (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270, 792–794 19 Sakurai, T. et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 20 Hinuma, S. et al. (1998) A prolactin-releasing peptide in the brain. Nature 393, 272–276 21 Civelli, O. (1998) Functional genomics: the search for novel neurotransmitters and neuropeptides. FEBS Lett. 430, 55–58 22 Nordquist, D.T. et al. (1998) cDNA cloning and characterization of three genes uniquely expressed in cerebellum by Purkinje neurons. J. Neurosci. 8, 4780–4789 23 Resh, M.D. (1999) Fatty acylation of proteins: new insights into membrane targeting of

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myristoylated and palmitoylated proteins. Biochim. Biophys. Act. 1451, 1–16 McKee, K.K. et al. (1997) Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 46, 426–434 Feighner, S.D. et al. (1999) Receptor for motilin identified in the human gastrointestinal system. Science 284, 2184–2188 Hosoda, H. et al. (2000) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J. Biol. Chem. 275, 21995–22000 Date, Y. et al. (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141, 4255–4261 Takaya, K. et al. (2000) Ghrelin strongly stimulates growth hormone (GH) release in humans. J. Clin. Endocrinol. Metab. 85, 4908–4911 Arvat, E. et al. (2000) Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)receptor ligand, strongly stimulates GH secretion in humans. J. Endocrinol. Invest. 23, 493–495

30 Date, Y. et al. (2000) Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem. Biophys. Res. Commun. 275, 477–480 31 Tivesten, A. et al. (2000) The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction. Endocrinology 141, 60–66 32 Van den Berghe, G. (2000) Novel insights into the neuroendocrinology of critical illness. Eur. J. Endocrinol. 143, 1–13 33 Tschöp, M. et al. (2000) Ghrelin induces adiposity in rodents. Nature 407, 908–913 34 Masuda, Y. et al. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem. Biophys. Res. Commun. 276, 905–908 35 Bernardis, L.L. and Bellinger, L.L. (1996) The lateral hypothalamic area revisited: ingestive behavior. Neurosci. Biobehav. Rev. 20, 187–287 36 Nakazato, M. et al. (2001) A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 37 Wren, A.M. et al. (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141, 4325–4328 38 Kamegai, J. et al. (2000) Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 4797–4800

Novel glucocorticoid receptor coactivator effector mechanisms Bethany D. Jenkins, Christian B. Pullen and Beatrice D. Darimont Glucocorticoids regulate numerous distinct physiological processes, most of which rely on the ability of the hormone-bound glucocorticoid receptor (GR) to change the expression of target genes in a cell- and promoter-dependent manner. The transcriptional activity of GR depends on coactivators that regulate transcription by remodeling chromatin or by facilitating the recruitment of the basal transcriptional machinery. Coactivators are often part of multiprotein complexes that are not specific for GR but also mediate the activity of other nuclear receptors (NRs) and unrelated transcription factors. Surprisingly, recent results reveal that the activity of coactivators might contribute to the receptor, promoter and cell specificity of NR action. The emerging picture shows coactivators as flexible, but precise, coordinators of complex and dynamic networks, in which transcriptional regulation by GR and other NRs is linked to other signaling pathways.

Bethany D. Jenkins Christian B. Pullen Beatrice D. Darimont* Institute of Molecular Biology and Dept of Chemistry, University of Oregon, Eugene, OR 97403-1229, USA. *e-mail: bead@ morel.uoregon.edu

Glucocorticoids mediate development and growth, regulate glucose and mineral homeostasis and modulate stress, inflammatory and immunological responses1. Their action is exerted by the glucocorticoid receptor (GR), which belongs to the large family of nuclear receptors (NRs). These receptors are structurally conserved, hormone-activated transcription factors2. At least two regions of GR possess intrinsic transcriptional activation functions (AFs). AF-2, in the C-terminal ligand-binding domain

(LBD) of GR, is directly controlled by the hormone. By contrast, AF-1 (also known as tau-1 or enh-2) is located at the GR N-terminus and can act independently of hormone. Although GR is expressed at essentially equal levels in almost all tissues, and glucocorticoids can freely cross cell membranes, transcriptional regulation by GR varies according to promoter and cell type3. Thus, specific cellular mechanisms must be in place to regulate the activity of GR. The transcriptional activity of GR is regulated by coactivators

Activation of GR by glucocorticoids is a multistep process that involves the ability of the receptor to recognize and bind these hormones, to undergo a hormone-dependent structural transformation, to translocate into the nucleus, and to identify target genes. There is increasing evidence that each step in this process is controlled by the interaction of GR with cofactors such as a heat shock protein 90 (hsp90)-containing chaperone complex, kinases, high mobility group (HMG) proteins and other transcription factors4–7. Additionally, the transcriptional activity of GR and other NRs

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Glossary ACTR: activator of the thyroid and retinoic acid receptor ADA: alteration/deficiency in activation AIB1: amplified in breast cancer 1 ARC: activator-recruited cofactor ASC-2: activating signal cointegrator 2 BRG1: Brahma-related gene 1 CBP: CREB-binding protein CREB: cAMP-response element-binding protein DRIP: vitamin D3 receptor-interacting protein GCN5: general control of amino acid synthesis 5 GRIP1: glucocorticoid receptor-interacting protein 1 L7/SPA: ribosomal protein L7/switch protein for antagonists NCoA: nuclear receptor coactivator NIDaux: auxiliary nuclear receptor interaction domain P/CAF: p300/CBP-associated factor p/CIP: p300/CBP-cointegrator associate protein PGC-1: peroxisome proliferator-activated receptorγ-coactivator RAC3: receptor-associated coactivator 3 SAGA: Spt-Ada-Gcn5-acetyltransferase SRC-1: steroid receptor coactivator 1 SWI/SNF: switch/sucrose non-fermentable TIF2: transcriptional intermediary factor 2 TRAM: thyroid receptor activator molecule TRAP: thyroid hormone receptor-associated protein

appears to depend on their interaction with coactivators and corepressors, which regulate the structure of chromatin and the recruitment of the basal transcriptional machinery8–10. Over 30 potential coactivators have been identified by their ability to bind various receptor domains and to alter the transcriptional activity of NRs in overexpression studies8–10. Although it was anticipated that coactivators would provide the means for cell- and promoter-specific regulation of NR activity, most coactivators are not receptor-specific, but also regulate the activity of many NRs and unrelated transcription factors. Furthermore, many coactivators are components of multiprotein complexes that have overlapping functions and NR-binding sites. Most of the known coactivators primarily interact with the NR AF-2 in the presence of activating hormones (agonists). Recently, a few have been identified that bind to other receptor domains or that recognize NRs bound to partial antagonists11–18. These coactivators appear to be more receptor specific than those operating through AF-2. Interactions between coactivators and GR

Although the mechanisms of coactivator action are under intense investigation, to date only a few coactivators have been analyzed for GR in more detail. These include the BRG1 (SWI/SNF) complex (see Glossary), the P/CAF (ADA/SAGA) complex, CBP/p300, the p160 coactivators and components of the DRIP (TRAP/ARC) complex. Components of the BRG1 (SWI/SNF) complex, an ATP-dependent chromatin remodeling complex, were among the first coactivators identified for GR (Refs 8,19,20). This complex directly interacts with the GR AF-1, and potentiates the activity of GR in yeast, mammalian cells and in vitro16. http://tem.trends.com

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Members of another chromatin remodeling complex, the P/CAF (ADA/SAGA) complex, were also shown to be important for GR-dependent transcriptional activation in yeast and mammalian cells8–10,17. The ability of this complex to regulate chromatin structure relies on the histone acetyltransferase (HAT) activity of its subunits, such as GCN5 in the yeast SAGA complex10. In addition, the P/CAF complex contains TATA box-binding protein (TBP)-associated factors (TAFs) that facilitate the recruitment of the basal transcriptional machinery21. Similar to the SWI/SNF complex, the P/CAF (ADA/SAGA) complex interacts with GR AF-1. These complexes appear to play overlapping roles in AF-1-mediated transcriptional regulation and can compensate for one another under certain conditions16. In addition to its interaction with AF-1, the P/CAF (ADA/SAGA) complex can be recruited to NRs through interaction with CBP/p300 and p160 coactivators9,10,22. CBP and p300 are HATs that interact stably or transiently with a large number of transcription factors, including NRs (Refs 9,10,23,24). Moreover, CBP has been shown to exist in a stable preformed complex with RNA polymerase II (Ref. 25). CBP/p300 is recruited to both GR and other NRs either directly, through AF-1, or indirectly through coactivators interacting with AF-2 (e.g. the p160 coactivator family18,26–28. At present, the p160 coactivator family contains three members: SRC-1/NCOA-1, GRIP1 (TIF2, NCoA-2) and p/CIP (RAC3, AIB1, ACTR, TRAM1, NCoA-3)9,10. Analogous to CBP/p300, these coactivators are HATs that interact transiently with a large number of NRs, other specific and general transcription factors, coactivators and an Arg-specific protein methylase (CARM1)9,10,29,30. Some p160 coactivators also appear to contact the AF-1 of several NRs and might be involved in coordinating AF-1 and AF-2 transcriptional activity18,26,31. However, their main interaction site is AF-2 in the receptor LBD, where they recognize a conserved, hormone-dependent interaction surface9. This interaction is mediated through conserved ‘LXXLL’ motifs, which are part of so-called NR-boxes32. The affinity of these NR-boxes for NRs is strongly receptor dependent and can be modulated by other coactivator sequences33–35. For example, the interaction of GR with GRIP1, which has three NR-boxes, requires both NR-box 3 and an additional GRIP1 region called NIDaux (Ref. 35). Thus, although p160 coactivators bind to a broad variety of NRs, their mechanisms of interaction are receptor specific36,37. In overexpression studies, the effect of p160 coactivators on GR-mediated transcriptional activity varies from various-fold increases in induction to inactivity or squelching, depending both on GR and coactivator expression levels, as well as on the promoter and cell type38. Consistent with these observations, mice with a targeted deletion of either SRC-1 or TRAM-1 show astonishingly distinct receptor- and tissue-specific phenotypes39–42.

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Unfortunately, however, the activity of GR in these mice has not yet been reported. In a yeast two-hybrid screen, DRIP150, a component of the DRIP complex, was identified as a potential coactivator of GR AF-1 (Ref. 13). The DRIP complex is related to the TRAP and ARC complexes, and these were originally isolated by their abilities to interact with AF-2 of the vitamin D receptor, the thyroid hormone receptor and a subset of other specific transcription factors, respectively9,10. GR AF1 mutants that do not interact with DRIP150 have reduced transcriptional activity, indicating that DRIP150 plays a role in mediating AF-1 activity in vivo13. DRIP150 also interacts with DRIP205, which is the component of the DRIP (TRAP/ARC) complex that binds directly to the AF-2 of several NRs. DRIP150 and DRIP205 activate GR synergistically and might be involved in coordinating the activities of AF-1 and AF-2 (Ref. 13). DRIP150 has also been found in other regulatory complexes, such as the NAT (negative regulator of activated transcription) complex, which represses activated transcription43. Whether this complex plays a role in mediating GR-dependent transcriptional repression remains to be determined. Other potential GR coactivators that are functionally interesting are: (1) the tissue-specific, thermogenic coactivator PGC-1, which interacts with both several NRs and the coactivators SRC-1 and CBP, and couples transcription and mRNA processing44–46; (2) L7/SPA, which binds to a region between the GR DNA- and ligand-binding domains, and might be involved in mediating tissue-specific agonist activity of the partial antagonist RU486 (Ref. 11); (3) the HIV-1 virion-associated protein Vpr, which might contribute to HIV-1-associated pathologies such as immune suppression, myopathy and muscle wasting47; and (4) the cancer-amplified transcriptional coactivator ASC-2, and the Pro-rich nuclear receptor coregulator (PNRC) that potentiate GR transcriptional activity and appear to interact with the AF-2 of NRs through LXXLL-independent mechanisms48,49. The roles of coactivators in GR-dependent transcriptional regulation are promoter and cell dependent

Glucocorticoids typically activate their target genes through the binding of hormone-liganded GR homodimers to imperfect palindromic sequences called glucocorticoid responsive elements (GREs). Most natural glucocorticoid-regulated promoters are complex and contain other cis-acting regulatory elements in addition to GREs. Some of the beststudied examples of these elements are the mouse mammary tumor virus (MMTV) long terminal repeat (LTR)50, and the promoters for Tyr aminotransferase (TAT)51 and phosphoenolpyruvate carboxykinase (PEPCK)52. In addition to transcriptional activation, GR can repress the transcription of target genes via http://tem.trends.com

multiple mechanisms. In the case of the GR-regulated genes encoding keratin53 and proopiomelanocortin54, repression is mediated by ‘negative GREs’ that are bound by either GR monomers or a combination of monomers and dimers, respectively. GR bound to ‘composite elements’, such as in the case of the gene encoding proliferin, can either activate or repress transcription, depending on interactions of the DNA-bound GR with other transcription factors (e.g. AP-1)55. One of the most important pharmacological roles of glucocorticoids is their antiinflammatory and immunosuppressive activity, which is mainly mediated by the ability of hormonebound GR to inhibit the transcriptional activity of nuclear factor κB (NF-κB) (p65–p50 heterodimers) or AP-1 (Jun–Fos heterodimers)1. Thus, both the type of GRE and the promoter context appear to influence which interaction surfaces are exposed by GR, and therefore which coactivators are recruited. The activation of the MMTV LTR strongly depends on its chromatin structure8,56. In the presence of chromatin, the rate-limiting step in the activation of MMTV LTR is the recruitment of the BRG1 complex by hormone-bound GR. Competition for this complex might be the main mechanism for progesterone-mediated repression of the MMTV LTR (Ref. 56). A minor portion of BRG1 co-purifies with the p160 coactivators SRC-1 and TIF2, which recruit CBP/p300 and the P/CAF complex57. Although SRC-1, CBP/p300 and the P/CAF complex are also able to remodel chromatin, they are not sufficient to activate chromatin-bound MMTV, but they might act in sequence with the BRG1 complex56. The phosphorylation of histone H1 in response to hormone is another important step in the activation of the MMTV LTR and might involve the GRfacilitated recruitment of a protein kinase56. In transient transfections, GR-dependent induction of the MMTV promoter in HeLa cells is repressed by the nuclear factor I (NFI)-C. Although this repression can be alleviated by overexpression of GR, CBP/p300 and the p160 coactivator SRC-1, overexpression of RAC3, another p160 coactivator, has no effect58. Transcription of the PEPCK gene is under multihormonal control, including stimulation by glucocorticoids and retinoic acid. Complete induction of the hepatic PEPCK gene by glucocorticoids requires the interaction of GR with two GREs, binding of four additional transcriptional regulators to so-called accessory factor-binding sites and recruitment of the coactivators SRC1 and GRIP1 (Refs 59,60). Glucocorticoid-mediated repression of a subset of keratin genes involves the binding of four GR monomers to the promoters of these genes. Whereas coexpression of the p160 coactivators SRC-1 and GRIP1 has no apparent effect, increasing concentrations of CBP enhance hormone-mediated repression of keratin promoters53. The ability of CBP

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to repress GR activity has also been demonstrated in other promoter and cell contexts61. Interestingly, in contrast to CBP, p300 potentiates GR activity in these studies, indicating that even these closely related coactivators can display distinct activities62. These examples demonstrate that GR-dependent promoters use different coactivator complexes with distinct functional properties. Thus, coactivators appear to contribute to the promoter and cellular specificity of the GR-mediated response to hormone. κB activity: GR-dependent repression of AP-1 and NF-κ competition for CBP/p300 and p160 coactivators?

Acknowledgements We thank R. Nissen and K. Yamamoto for sharing results before publication, and J. Davenport, D. Hawley and T. Stevens for critical reading of the manuscript. B.D.D. is a special fellow of the Leukemia and Lymphoma Society and is supported by grants from the Medical Research Foundation of Oregon and American Heart Association (0060423Z).

Despite extensive research efforts, the mechanism of GR-dependent repression of NF-κB or AP-1 activity remains to be determined. Several models for the role of GR have been suggested, including prevention of NF-κB or AP-1 DNA binding, upregulation of the NF-κB inhibitor IκBα, and interference with the Jun N-terminal kinase that is required for AP-1 activation63. Recently, a model has been proposed in which GR competes with NF-κB and AP-1 for a limiting supply of coactivators64,65. The basis for this model is that GR, AP-1 and NF-κB are all functionally dependent on SRC-1 and CBP/p300. Moreover, in agreement with this ‘competition’ model, overexpression of SRC-1 and CBP appears to release GR-mediated repression of AP-1 and NF-κB. However, this model cannot explain why GR-dependent repression of NF-κB and AP-1 activity is promoter specific, or why repression requires the presence of other GR domains apart from the LBD, which is sufficient to interact with SRC-1 and the SRC-1–CBP/p300 complex. A recent study by De Bosscher et al.66 demonstrated that the ability of GR to repress NF-κB activity can be independent of the concentration of CBP, p300 and SRC-1, and that increasing concentrations of GR do not compete with the binding of CBP and SRC-1 to NF-κB. These results challenge the generality of the competition model. Most protein interaction studies point to an alternative ‘tethering model’ in which GR interacts with DNA-bound AP-1 or NF-κB and inhibits their

References 1 Kellendonk, C. et al. (1999) Mutagenesis of the glucocorticoid receptor in mice. J. Steroid Biochem. Mol. Biol. 69, 253–259 2 Whitfield, G.K. et al. (1999) Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function. J. Cell. Biochem. (Suppl. 32–33), 110–122 3 Bamberger, C.M. et al. (1996) Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 17, 245–261 4 Pratt, W.B. (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc. Soc. Exp. Biol. Med. 217, 420–434 5 Bodwell, J.E. et al. (1998) Glucocorticoid receptor phosphorylation: overview, function and cell cycledependence. J. Steroid Biochem. Mol. Biol. 65, 91–99 6 Boonyaratanakornkit, V. et al. (1998) Highhttp://tem.trends.com

7

8

9

10

11

125

transcriptional activity directly. GR-mediated repression of interleukin 1β (IL-1β)-induced GM–CSF (granulocyte–macrophage colonystimulating factor) expression involves GRdependent inhibition of histone H4 acetylation67. This inhibition appears to be caused by the ability of GR to block the HAT activity of CBP directly and to recruit the histone deacetylase (HDAC2) to the p65–CBP HAT complex. Alternatively, Nissen and Yamamoto demonstrated that inhibition of NF-κB activity might occur at the level of transcription initiation68. With the help of chromatin-dependent immunoprecipitations, they obtained results showing that GR reduces transcriptional initiation at the NF-κB promoter by interfering with Ser-2 phosphorylation of the RNA polymerase II C-terminal domain. As it is unlikely that GR dephosphorylates RNA polymerase II directly, GR might interfere with the activity of a kinase, or recruit a novel co-repressor that has phosphatase activity. Thus, multiple, perhaps promoter-specific, mechanisms might be involved in GR-mediated repression, and it is probable that new mechanisms remain to be discovered. Concluding remarks

The GR and other NRs are much more than simple on/off switches that translate the presence of hormones into changes in gene expression. They are part of dynamic regulatory networks that link many transcription factors and signaling pathways together to produce distinct functional consequences. The coordinators of these networks are coactivators, a fast growing group of proteins that initially appeared to act non-specifically and to be functionally redundant. However, this view is being updated by recent results demonstrating that even very closely related coactivators have distinct receptor-, promoterand cell-specific activities. The future challenge will be to identify experimental strategies that enable a physiological, relevant analysis of these complex regulatory events, allowing us to decipher the underlying molecular mechanisms.

mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol. Cell. Biol. 18, 4471–4487 McEwan, I.J. et al. (1997) Mechanism of gene expression by the glucocorticoid receptor: role of protein–protein interactions. BioEssays 19, 153–160 Collingwood, T.N. et al. (1999) Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. J. Mol. Endocrinol. 23, 255–275 Glass, C.K. and Rosenfeld, M.G. (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 McKenna, N.J. et al. (1999) Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J. Steroid Biochem. Mol. Biol. 69, 3–12 Jackson, T.A. et al. (1997) The partial agonist

12

13

14

15

activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol. Endocrinol. 11, 693–705 Endoh, H. et al. (1999) Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α. Mol. Cell. Biol. 19, 5363–5372 Hittelman, A.B. et al. (1999) Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. EMBO J. 18, 5380–5388 Lanz, R.B. et al. (1999) A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97, 17–27 Moilanen, A.M. et al. (1998) Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription. Mol. Cell. Biol. 18, 5128–5139

126

Review

16 Wallberg, A.E. et al. (2000) Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau1 activation domain. Mol. Cell. Biol. 20, 2004–2013 17 Henriksson, A. et al. (1997) Role of the Ada adaptor complex in gene activation by the glucocorticoid receptor. Mol. Cell. Biol. 17, 3065–3073 18 Almlof, T. et al. (1998) Role of important hydrophobic amino acids in the interaction between the glucocorticoid receptor tau-1-core activation domain and target factors. Biochemistry 37, 9586–9594 19 Cairns, B.R. et al. (1996) Essential role of Swp73p in the function of yeast Swi/Snf complex. Genes Dev. 10, 2131–2144 20 Yoshinaga, S.K. et al. (1992) Roles of SWI1, SWI2, and SWI3 proteins for transcriptional enhancement by steroid receptors. Science 258, 1598–1604 21 Ogryzko, H. et al. (1998) Histone-like TAFs within the PCAF histone acetylase complex. Cell 94, 35–44 22 Chen, V.V. et al. (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90, 569–580 23 Goodman, R.H. and Smolik, S. (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 24 Shikama, N. et al. (1997) The p300/CBP family: integrating signals with transcription factors and chromatin. Trends Cell Biol. 7, 230–236 25 Kee, B.L. et al. (1996) Adaptor-mediated recruitment of RNA polymerase II to a signaldependent activator. J. Biol. Chem. 271, 2373–2375 26 Kobayashi, Y. et al. (2000) p300 mediates functional synergism between AF-1 and AF-2 of estrogen receptor α and β by interacting directly with the N-terminal A/B domains. J. Biol. Chem. 275, 15645–15651 27 Smith, C.L. et al. (1996) CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptordependent transcription. Proc. Natl. Acad. Sci. U. S. A. 93, 8884–8888 28 Yao, T.P. et al. (1996) The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc. Natl. Acad. Sci. U. S. A. 93, 10626–10631 29 Chen, D. et al. (1999) Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 30 Chen, H. et al. (1999) Regulation of hormoneinduced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98, 675–686 31 Ma, H. et al. (1999) Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol. Cell. Biol. 19, 6164–6173 32 Heery, D.M. et al. (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 33 Darimont, B.D. et al. (1998) Structure and specificity of nuclear receptor–coactivator interactions. Genes Dev. 12, 3343–3356 34 McInerney, E.M. et al. (1998) Determinants of coactivator LXXLL motif specificity in nuclear http://tem.trends.com

TRENDS in Endocrinology & Metabolism Vol.12 No.3 April 2001

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

receptor transcriptional activation. Genes Dev. 12, 3357–3368 Hong, H. et al. (1999) An additional region of coactivator GRIP1 required for interaction with the hormone-binding domains of a subset of nuclear receptors. J. Biol. Chem. 274, 3496–3502 Korzus, E. et al. (1998) Transcription factorspecific requirements for coactivators and their acetyltransferase functions. Science 279, 703–707 Perissi, V. et al. (1999) Factor-specific modulation of CREB-binding protein acetyltransferase activity. Proc. Natl. Acad. Sci. U. S. A. 96, 3652–3657 Szapary, D. et al. (1999) Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists, and residual agonist activity of antagonists, for glucocorticoid receptor-regulated gene expression. Mol. Endocrinol. 13, 2108–2121 Xu, J. et al. (1998) Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 279, 1922–1925 Weiss, R.E. et al. (1999) Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J. 18, 1900–1904 Qi, C. et al. (1999) Mouse steroid receptor coactivator-1 is not essential for peroxisome proliferator-activated receptor alpha-regulated gene expression. Proc. Natl. Acad. Sci. U. S. A. 96, 1585–1590 Xu, J. et al. (2000) The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 97, 6379–6384 Sun, X. et al. (1998) NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription. Mol. Cell 2, 213–222 Knutti, D. et al. (2000) A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Mol. Cell. Biol. 20, 2411–2422 Puigserver, P. et al. (1999) Activation of PPARγ coactivator-1 through transcription factor docking. Science 286, 1368–1371 Monsalve, M. et al. (2000) Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol. Cell 6, 307–316 Kino, T. et al. (1999) The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J. Exp. Med. 189, 51–62 Lee, S.K. et al. (1999) A nuclear factor, ASC-2, is a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo. J. Biol. Chem. 274, 34283–34293 Zhou, D. et al. (2000) PNRC: a proline-rich nuclear receptor coregulatory protein that modulates transcriptional activation of multiple nuclear receptors including orphan receptors SF1 steroidogenic factor 1 and ERRα 1 estrogen related receptor α-1. Mol. Endocrinol. 14, 986–998 Zaret, K.S. and Yamamoto, K.R. (1984) Reversible and persistent changes in chromatin structure accompany activation of a glucocorticoiddependent enhancer element. Cell 38, 29–38

51 Jantzen, H.M. et al. (1987) Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene. Cell 49, 29–38 52 Hanson, R.W. and Reshef, L. (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem. 66, 581–611 53 Radoja, N. et al. (2000) Novel mechanism of steroid action in skin through glucocorticoid receptor monomers. Mol. Cell. Biol. 20, 4328–4339 54 Drouin, J. et al. (1993) Novel glucocorticoid receptor complex with DNAelement of the hormonerepressed POMC gene. EMBO J. 12, 145–156 55 Diamond, M.I. et al. (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249, 1266–1272 56 Fryer, C.J. and Archer, T.K. (1998) Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex. Nature 393, 88–91 57 McKenna, N.J. et al. (1998) Distinct steady-state nuclear receptor coregulator complexes exist in vivo. Proc. Natl. Acad. Sci. U. S. A. 95, 11697–11702 58 Chaudhry, A.Z. et al. (1999) Nuclear factor Imediated repression of the mouse mammary tumor virus promoter is abrogated by the coactivators p300/CBP and SRC-1. J. Biol. Chem. 274, 7072–7081 59 Sugiyama, T. et al. (2000) Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene. J. Biol. Chem. 275, 3446–3454 60 Wang, J.C. et al. (1998) SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. J. Biol. Chem. 273, 30847–30850 61 Kino, T. et al. (1999) Conditional modulation of glucocorticoid receptor activities by CREBbinding protein (CBP) and p300. J. Steroid Biochem. Mol. Biol. 70, 15–25 62 Ugai, H. et al. (1999) The coactivators p300 and CBP have different functions during the differentiation of F9 cells. J. Mol. Med. 77, 481–494 63 De Bosscher, K. et al. (2000) Mechanisms of antiinflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J. Neuroimmunol. 109, 16–22 64 Kamei, Y. et al. (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414 65 Sheppard, K.A. et al. (1998) Nuclear integration of glucocorticoid receptor and nuclear factor-κB signaling by CREB-binding protein and steroid receptor coactivator-1. J. Biol. Chem. 273, 29291–29294 66 De Bosscher, K. et al. (2000) Glucocorticoids repress NF-κB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc. Natl. Acad. Sci. U. S. A. 97, 3919–3924 67 Ito, K. et al. (2000) Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12. Mol. Cell. Biol. 20, 6891–6903 68 Nissen, R.M. and Yamamoto, K.R. (2000) The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 14, 2314–2329