Nuclear receptor coregulators as a new paradigm for therapeutic targeting☆
Introduction
The significance of understanding transcriptional regulation by the nuclear hormone receptors (NRs) is underscored by the diverse diseases, such as cancer, where numerous aberrations in hormone signaling pathways are uncovered. Transcriptional regulation by NRs involves ordered and dynamic protein-protein interactions between the receptor, associated coregulators, and the RNA polymerase II transcriptional machinery at the chromatin of target genes. Many coregulators possess enzymatic activities or recruit multi-subunit enzymatic protein complexes to mediate specific chromatin modifications that result in either transcriptional activation or repression (see below).
Coregulators can be divided into two general classes, namely, coactivators and corepressors. Coactivators are generally characterized by their ability to enhance NR transactivation by interacting with the N-terminus and/or the C-terminal ligand binding domain (LBD) of agonist-bound NRs. The counterparts of coactivators, called corepressors, were identified as mediators for selectively repressing NR-dependent gene transcription through interaction with unliganded or antagonist-bound (or in some cases, agonist-bound) NRs on their target genes [1].
Because many coregulators influence the activity of multiple nuclear hormone receptors and thus the transcriptional output of many gene networks, it is not surprising that disruption of their normal function or expression can contribute to a vast spectrum of physiological abnormalities and diseases. Many studies using mouse models support this notion and have contributed to our understanding of coregulators for normal biological function. For example, gene knockout studies have demonstrated important roles for individual members of the p160 family of coactivators (see below) in hormonal responses and organ developments during reproduction, metabolism, and growth [2]. Furthermore, the phenotypic defects were not restricted to hormone-regulated tissues and processes, reflecting in some circumstances a more general role played by the coregulators in control of gene expression. While we acknowledge that many coregulators associate with and mediate the functions of NRs besides steroid receptors, their aberrant expression and function appear to be best understood so far in the steroid hormone responsive human malignancies such as breast cancer and prostate cancer (e.g. the p160/SRC family) or metabolism and energy homeostasis (e.g. PGC-1). Here, we outline the structure and function of coregulators that can thus be considered as highly attractive and promising, new therapeutic targets (Fig. 1, Fig. 2).
Section snippets
Coactivators — structure, function and therapeutic implications
Enzymatic modification of chromatin structure is at the heart of gene regulation at the transcriptional level. Coactivators can promote gene-specific NR-mediated transcription via several activities. Changes in post-translational modifications on core histone tails – particularly acetylation and methylation – serve as a crucial step in the remodeling of chromatin structure during gene expression. Loss-of-function experiments revealed that the histone acetylase (HAT) activities of the general
NCoR and SMRT — repressors of unliganded and antagonist-bound NRs
The first NR corepressors were identified based on their ability to mediate transcriptional repression by unliganded thyroid hormone (TR) and retinoid acid receptors. The aptly named NR corepressor (NCoR) and silencing mediator for RAR and TR (SMRT) contain multiple repression domains that serve as docking platforms for recruitment of additional components in the corepressor complex including HDAC and mSin3. Later studies discovered that NCoR and SMRT can interact with additional NRs in the
Concluding remarks
Substantial research progress in NR coregulator function and mechanisms provided valuable insights into their contributions to disease development. This review focused on thus far relatively well-characterized representatives from both classes of coregulators and coincidentally, the evidence we present here attribute to their pathological and clinical relevance in various malignancies. However, as illustrated by the coactivator PGC-1α, some coregulators have established roles in physiological
Acknowledgments
This work was supported in part by NIH grants R01DK53528 (M.L. Privalsky), R01CA113860, R01CA134766 and R01DK060019 (H-W Chen), and DoD grant W81XWH-07-1-0312 (J. X Zou).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Development of Novel Therapeutic Strategy by Regulating the Nuclear Hormone Receptors”.