Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators

0163-769X/04/$20.00/0 Printed in U.S.A. Endocrine Reviews 25(1):45–71 Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2003-0023 Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators CAROLYN L. SMITH AND BERT W. O’MALLEY Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 Ligands for the nuclear receptor superfamily control many aspects of biology, including development, reproduction, and homeostasis, through regulation of the transcriptional activity of their cognate receptors. Selective receptor modulators (SRMs) are receptor ligands that exhibit agonistic or antagonistic biocharacter in a cell- and tissue context-dependent manner. The prototypical SRM is tamoxifen, which as a selective estrogen receptor modulator, can activate or inhibit estrogen receptor action. SRM-induced alterations in the conformation of the ligand-binding domains of nuclear receptors influence their abilities to interact with other proteins, such as coactivators and corepressors. It has been postulated, therefore, that the relative balance of coactivator and core- pressor expression within a given target cell determines the relative agonist vs. antagonist activity of SRMs. However, recent evidence reveals that the cellular environment also plays a critical role in determining SRM biocharacter. Cellular signaling influences the activity and subcellular localization of coactivators and corepressors as well as nuclear receptors, and this contributes to gene-, cell-, and tissue-specific responses to SRM ligands. Increased understanding of the effect of cellular environment on nuclear receptors and their coregulators has the potential to open the field of SRM discovery and research to many members of the nuclear receptor superfamily. (Endocrine Reviews 25: 45–71, 2004) I. Introduction II. Biology of Selective Receptor Modulators (SRMs) A. Selective ER modulators (SERMs) B. Selective tissue estrogenic activity regulators (STEARs) C. Selective PR modulators (SPRMs) D. Selective AR modulators (SARMs) E. Selective peroxisome proliferator-activated receptor modulators (SPARMs) F. Other SRMs III. Mechanisms of SRM Action on Steroid Receptors A. General steroid hormone action B. Effect of ligand on receptor structure C. Coactivators D. Corepressors E. SRM hypothesis IV. Molecular Basis of Cellular Selectivity A. Receptor-selective recruitment of coactivators B. Influence of DNA on coregulator interaction C. Effect of cell signaling on receptor-coregulator interactions D. Relative coregulator expression V. Lessons Learned from Coregulator Knockout Mice VI. Concluding Remarks I. Introduction N UCLEAR RECEPTORS COMPRISE a large family of eukaryotic transcription factors, and those for whom ligands have been identified are broadly exploited to manipulate various aspects of human biology (1, 2). There is a well-developed pharmacology for many of the nuclear receptors, and the identification of natural and high-affinity synthetic agonistic ligands for these receptors has enabled many studies of the biological effects of these nuclear receptors in vitro and in vivo. The availability of antagonists also has been important. In experimental studies they proved to be useful tools for validating that an effect under consideration is indeed mediated by a nuclear receptor of interest. Clinically, they have been used to block or inhibit undesirable physiological actions of receptors. For instance, tamoxifen, due to its ability to inhibit estrogen receptor (ER) action, is used widely in the treatment and prevention of breast cancer. Careful examination of the selective biological effects of tamoxifen (e.g., estrogen-like activity in the uterus but antiestrogen-like effects in the breast) led to the emergence of the concept of selective ER modulators or SERMs (see below). The molecular mechanisms through which selective effects are obtained has been the topic of intense investigation with the result that not only do we have at least a basic under- Abbreviations: AF-1 and -2, Activation function 1 and 2; AIB1, amplified in breast cancer 1; AP-1, activator protein 1; AR, androgen receptor; CARM1, coactivator-associated arginine (R) methyltransferase-1; CBP, cAMP response element binding protein (CREB)-binding protein; ChIP, chromatin immunoprecipitation; CNS, central nervous system; DRIP, vitamin D receptor-interacting protein; E2, 17␤-estradiol; EGF, epidermal growth factor; ER, estrogen receptor; ERE, estrogen response element; GR, glucocorticoid receptor; GRIP, GR-interacting protein; 4HT, 4-hydroxytamoxifen; IKK, I␬B kinase; LBD, ligand-binding domain; MEF, mouse embryo fibroblast; MEK, MAPK kinase; NCoR, nuclear receptor corepressor; PCOS, polycystic ovarian syndrome; PGC-1, PPAR␥ coactivator-1␣; PPAR, peroxisome proliferator-activated receptor; PR, progesterone receptor; RAC3, receptor associated coactivator; RAR, retinoic acid receptor; RIP, receptor-interacting protein; SARM, selective AR modulator; SERM, selective ER modulator; SGRM, selective GR modulator; SMRT, silencing mediator of retinoic acid and thyroid hormone receptor; SPRM, selective PR modulator; SRC, steroid receptor coactivator; SRM, selective receptor modulator; TIF, transcriptional intermediary factor; TR, thyroid hormone receptor; TRAP, TRassociated protein. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. 45 46 Endocrine Reviews, February 2004, 25(1):45–71 standing of how the selective nature of SERM activities is achieved, we have now progressed to a point at which the stage is set to pursue the identification and development of selective receptor modulators (SRMs) for a host of other nuclear receptors. The driving force in this research is the desire to obtain agents that can better separate desired nuclear receptor effects from those that are undesirable. Indeed, the lessons learned from SERMs provide a framework in which to pursue the development of other SRM ligands with high binding affinity to the receptor of interest. The experience with SERMs suggests that compounds with selective activities are likely to be of intense clinical and economic interest, thereby stimulating significant research in this area in both the basic science and pharmacological arenas. II. Biology of Selective Receptor Modulators (SRMs) A. Selective ER modulators (SERMs) Estrogens have long been recognized to play critical roles during development and reproduction, as well as in the growth and maintenance of the skeleton. In addition, evidence of the contribution of estrogens to the normal function of the cardiovascular system and central nervous system (CNS), including cognition and potential delayed onset of Alzheimer’s disease, and a variety of other tissues and organs (e.g., colon) indicates that this class of steroids, and by extension its re (...truncated)