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Coregulators: From Whence Came These "Master Genes"

Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: B. W. O’Malley, Baylor College of Medicine, Department of Cell Biology, 1 Baylor Plaza, Houston, Texas 77030. E-mail: berto{at}bcm.tmc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
IT IS NOW OVER a decade since the first nuclear receptor (NR) coactivator, steroid receptor coactivator 1 (SRC-1), was cloned and discovered to be a new type of transcription factor that does not bind DNA, but rather, binds directly or indirectly to NRs to mediate their transcriptional potency. The NR coactivators belong to a class of molecules now termed "coregulators." Employing an operational definition, we define coactivators as molecules that enhance transcription, and corepressors as molecules that repress transcription. Current evidence indicates that this operational definition can be modified by gene, cell, and signaling context for any one coregulator. Our current understanding is that NRs and other DNA-binding transcription factors (TFs) search out the target genes to be regulated by binding to specific DNA sequences (or other TFs at such sequences) termed "TF-response elements" (1 ); the second job of NRs is to recruit the coregulators that perform all of the subsequent reactions needed to induce or repress expression of genes. Initially, we believed that coactivators were simply adapters that stabilized the general transcription machinery at the TATA box. This explanation proved to be incorrect. Over the past decade, the mechanistic importance of coregulators has expanded logarithmically, and we now realize that they perform virtually all of the reactions needed for control of enhancer-dependent gene expression. In this minireview, I will emphasize the history of coactivators, but corepressors are equally important for gene regulation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
Coactivators exist and function in large multiprotein complexes; these coactivator complexes are recruited to the target gene in rapid sequence by NRs (2) and contain the many enzyme capacities required for the gene’s expression. Subreactions of transcription mediated by coactivator complexes include chromatin modification and remodeling, initiation of transcription, elongation of RNA chains, RNA splicing, and finally, termination of the transcriptional response. Recently, coactivators even have been reported to control cellular reactions outside the nucleus such as mRNA translation, mitochondrial function, and motility (3, 4). The importance of these molecules to molecular endocrinology suggests that we might reflect on a few selected advances that have promoted the historical development of this field. In the following minireview, there is no opportunity to discuss all of the numerous excellent studies that played a role in the development of the coregulator field; space considerations allow only a presentation of my personal views of selected key events that advanced coregulators as mediators of NR function (Fig. 1). Because experiments on both coactivators and coregulators advanced the coregulator field in concert, we will consider the intertwined experimental history of both in a temporal fashion.

View larger version (38K): [in this window] [in a new window]   Fig. 1. NR Function: An Evolving Complexity Represented in the upper panel (1975), the mechanism of NR action was known to be at the level of DNA to induce new mRNAs. It was assumed that the receptor somehow induced RNA Pol II to transcribe target genes. The NR was considered to possibly directly contact Pol II to initiate transcription, but no details were known. Represented in the middle panel (1990), we now knew that hormone response elements (HREs) were the DNA landing places for NRs. The general transcription factors (GTFs; includes TFIID, which is comprised of TBP, and associated TAFs) were known to bind to the proximal promoter (TATA box) and bring Pol II to the gene. It was considered that the NR acted through some unknown adaptor factor that touched both the NR and the GTFs, stabilizing the GTFs and bringing Pol II repeatedly to the gene for transcription. Presently (2007), in the middle panel, we have a more complex idea of NR-mediated transcription. The NR’s role is to find the target genes and, instead of recruiting an adaptor, the NR recruits a large series (n) of coactivator complexes to the gene. The recruitment of complexes occurs in sequence and the kinetics are rapid (t1/2 15 sec). Most of the individual coactivators [e.g. steroid receptor coactivator (SRC)-1, SRC-2, p300, pCAF, etc.] are enzymes that 1) modify the local chromatin (acetylation, methylation, phosphorylation, etc.) and 2) provide protein reactants for controlling initiation of transcription by Pol II, elongation of RNA chains, RNA splicing, termination of transcription, etc. Over the past 37 yr, nothing has been found wrong with the initial hypotheses for NR action, but the complexity has increased greatly. Our picture of NR mechanisms is now known in considerable detail. H, Hormone; TA, TBP-associated protein; TB, TBP; CB, coactivator binding protein; CARM, coactivator arginine methylase; SRCP, SRC protein.

	MASTER GENES?

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

	EARLY RELATED EXPERIMENTS

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
Our laboratory first became interested in receptor-associated nuclear proteins in the early 1970s, when we discovered that progesterone-receptor complexes bound to nuclear DNA as a complex with associated oviductal proteins that we termed "acceptor proteins" (6). These acceptor proteins were of the nonhistone variety and were present in different concentrations in the nuclei of target and nontarget tissues. Our attempts at purifying an acceptor protein were unsuccessful due to the tremendous and puzzling heterogeneity of the molecules. We could not understand why they appeared so numerous and difficult to characterize via charge and size separation columns. In 1989, the laboratory of Murray and Towle (7) published similar results that thyroid hormone receptor (TR) associated with heat-denaturable proteins in crude nuclear extracts of tissues in a manner altered by ligand. It was not until more than two decades later that we realized and confirmed that these acceptor sites that we were investigating were actually part of the hundreds of NR coactivators now known to be present in nuclear chromatin.

Almost always in biology, progress occurs as the result of cumulative data produced by many laboratories, which then eventually evolve into a final molecular concept. It is my opinion that the laboratory of Ma and Ptashne (8) provided some of the first guiding principles, demonstrating in yeast cells that protein-protein interactions between TFs can directly control inhibition or activation of genes; they showed that GAL80, an inhibitor of the yeast transcriptional activator GAL4, can be converted into an activator by insertion of an acidic activating sequence (8). This hybrid activator did not bind to DNA directly but was brought to DNA by interacting with a derivative of GAL4 that bound to both the GAL80 and DNA. The work of Ma and Ptashne rekindled the interest of a number of laboratories working on TF-associated proteins in animal cells.

A series of papers beginning in the 1990s presented excellent examples of Drosophila proteins that bind to TATA-binding protein (TBP), termed TAFs, and are part of the TFIID complex that interacts with the promoter (TATA box) via TBP (9). The laboratory of Tjian and associates (9) showed that they regulated basal promoter activity, and they termed them "coactivators" in some of their publications. However, they are not coactivators as we now know them in the NR field. They help TBP during basal transcription to recruit polymerase II (Pol II) to the promoter start site for transcription (and even receive some signals from upstream kinases, etc.), but they were not the long-sought enhancer-regulatory proteins that mediate signal-dependent regulation of genes in mammals. The TAFs, however, have no common sequence homology with the 285+ classical mammalian coregulators isolated subsequently and that regulate genes via upstream enhancer elements.

In another study, B cell-restricted activity required for high levels of octamer/Oct-dependent transcription from an Ig heavy chain (IgH) promoter was detected in an in vitro system by the laboratory of Roeder and co-workers (10). The factor responsible for this activity was designated Oct coactivator from B cells (OCA-B) and was shown to stimulate transcription from an IgH promoter in conjunction with either Oct-1 or Oct-2 but showed no significant effect on the octamer/Oct-dependent transcription of the ubiquitously expressed histone H2B promoter. OCA-B was likely a coactivator-type of protein activity. During this time period, receptor-receptor squelching experiments were published by our laboratory (11) and by the laboratory of Chambon and associates (12); the results of these squelching experiments were as might be predicted from Ptashne’s earlier yeast studies and furthered the idea that undiscovered cellular mediators of NR actions might exist in mammalian cells.

	EXPERIMENTS TOWARD COREGULATORS

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
The ability of NRs to repress transcription has been studied since the 1980s, mostly with TR, but molecular mechanisms were scarce. In 1992, two papers established some principles for NR regulation by corepressors. In these publications, mutagenesis approaches in yeast and mammalian cells and cell-free proteolytic and epitope mapping analyses established that progesterone receptor and retinoic acid receptor contain a repressor domain in the carboxy-terminal tail of the receptor that silences its transactivation potential (13); this silencing was relieved by a conformational change induced by agonist (but not antagonist) in which the tail flips over like the lid of a box (confirmed some years later by x-ray crystallization) (14). This newly formed surface was later shown to provide a landing platform for coregulators. Next, our laboratory published proof-of-principle experiments for a cellular corepressor protein using two NRs (estrogen receptor and progesterone receptor). In yeast cells, we showed that a protein, termed "SSN6," binds to the TAF1 activation domain of estrogen receptor and suppresses hormone-dependent activity (15). Mutations that prevented this protein-protein interaction increased NR activity by 4 orders of magnitude in the presence of hormone, but not in the presence of antihormones. The data suggested that the role of hormone is 2-fold: it promotes DNA binding and also induces a conformational change in receptor that overcomes the corepressor function in cells.

Soon after the above publications, Yamamoto and associates (16) reported that hormone-independent immunoprecipitation of glucocorticoid receptor derivatives from wild-type (SWI+) yeast extracts coprecipitated the SWI3 a protein(s) that binds to RNA polymerase. Receptor-SWI3 complexes were not detected in swi1- or swi2-mutant strains, implying for the first time that a complex of multiple proteins may associate with the receptor. Prior incubation of a Drosophila embryo transcription extract with the yeast SWI3-specific antibody inhibited receptor function in vitro whereas the antibody had no effect if added after formation of the initiation complex. Thus, the glucocorticoid receptor appeared to require an interaction with one or more SWI proteins to function positively in yeast.

In 1994, the Goodman laboratory identified cAMP-response element-binding protein (CREB)-binding protein (CBP), an important nuclear protein of M_r 265,000, which bound specifically to the protein kinase A-phosphorylated form of CREB and also interacted with the basal transcription factor TFIIB (17). Consistent with its role as a coregulator, CBP augmented the activity of phosphorylated CREB to activate transcription of cAMP-responsive genes. Although no studies were carried out with NRs at this juncture, subsequent studies have revealed that CBP and p300 are general coregulators that, in one way or another, appear to be ubiquitous integrative components in virtually all eukaryotic transcription complexes.

The Brown laboratory (18) used fractionated cell extracts to reveal 160,000-Da estrogen-interacting proteins termed "ERAP160s." The protein fraction exhibited estradiol-dependent binding to the receptor. Mutational analysis of the estrogen receptor showed that its ability to activate transcription correlated with its ability to bind ERAP160. Antiestrogens were unable to promote ERAP160 binding. This significant publication suggested that ERAP160 proteins could be mediators of estradiol-dependent transcriptional activation by the estrogen receptor. Although the laboratory did not purify ERAP160 or clone the molecules, this publication was an important encouragement in the race by multiple laboratories to identify a specific coactivator molecule.

During this time frame, we were investigating a molecule that we found to function as a coactivator protein by binding and activating the TAF2 of estrogen receptor in yeast and primate cells (19). This was a yeast protein, termed "SPT6," that interacted directly and specifically with the hormone-binding domain of human estrogen receptor (TAF2) in vitro and in vivo and was a mediator of hormonal signal transmission. The study was critical to allow us to predict the criteria by which a mammalian coactivator could be identified.

In the same month as our publication of SPT6 coactivator, we published the first biochemical discovery of a soluble cellular corepressor for a NR (hTR) and accurately predicted the currently accepted concept for coregulator function: that corepressor exchange with a coactivator is the mechanism for ligand-induced activation of NRs in primate cells (20). The existence of corepressors was substantiated definitively by laboratories of Glass and associates (21) and of Chen and Evans (22) when they separately published the clonings of two specific and important corepressors, silencing mediator of retinoid and TR and NR corepressor.

A significant advancement toward coactivators was provided by Moore and co-workers (23) when they used a yeast interaction trap to isolate partial clones encoding peptides that interacted with the ligand-binding domain of the rat TR ß. Several related proteins, called TR-interacting proteins, were isolated from independent selections carried out either in the presence or absence of T₃. The TR-interacting proteins were shown to be dependent on hormone (T₃) for binding the TR. Although no characterizations were performed, a considerable number of these proteins represented peptide fragments of what were later proven to be authentic NR coregulators.

The laboratory of Parker and associates (24) characterized a novel nuclear protein, receptor-interacting protein 140 (RIP140), that specifically interacts in vitro with the activation function 2 domain of the estrogen receptor. This interaction was increased by estrogen, but not by antiestrogens, and the in vitro binding capacity of mutated estrogen receptors for RIP140 correlated with their ability to stimulate transcription. Because RIP140 interacted with estrogen receptor in intact cells, they originally suggested it might be a coactivator for NRs. Later, RIP140 was shown to be a corepressor (37). Recently, Parker and co-workers (24 have shown that the RIP140 corepressor is a protein of major biological importance for adipogenesis and reproduction.

At that time in 1995, an authenticated NR-interacting coregulator (SRC-1) was finally cloned (25). From this point forward, recruitment of coactivators was accepted as the mechanism for the gene-inductive function of NRs, thus providing the missing cornerstone in the hormone action pathway. The focus of authenticity is directed to SRC-1 because in one relatively short paper, the following criteria for coactivators were substantiated: 1) coactivators bind to NRs (directly or indirectly); 2) coactivators do not bind to DNA directly; 3) agonist ligands promote coactivator binding to NRs; 4) antagonist ligands inhibit binding of coactivators to receptors; 5) coactivators are able to reverse receptor-receptor squelching; 6) overexpression of coactivators greatly enhances transcriptional capacity; and 7) coactivator dominant-negative molecules knock down endogenous ligand-dependent NR function when introduced into cells.

	THE ERA OF COREGULATOR PHYSIOLOGY

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
Our laboratory (26, 27) then went on to prove that coactivators are physiological regulators in vivo in animals and that even closely related coactivators (i.e. SRC-1 and SRC-3) are nonredundant and have differing specific cellular gene-regulatory functions. For the most part, these newly emerging coactivators were shown to be enzymes by multiple groups (28, 29, 30, 31) and to function as large molecular complexes of proteins (32, 33). Interestingly, regulation of the cellular levels of coregulators occurs not via traditional transcriptional mechanisms, but rather, at the level of their degradation (34). The stage was now set for the plethora of studies pertaining to coregulator biology that were published over the next decade; this work illustrated the great importance of coregulators as master genes in all phases of normal physiology and medicine, including cancer, metabolism, cardiovascular, gastrointestinal, reproduction, neurology, genetics, and toxicology.

	MASTER GENES EXIST

TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 
The elucidation of coactivator function allowed a new understanding that coactivators were not just adaptors for upstream regulatory sequence communication to TBP as previously thought (35) but were major regulators and coordinators of many aspects of hormone-receptor physiology, including the concepts of tissue specificity of response, selective receptor modulator function, hormone inductive kinetics, integration of membrane and nuclear signaling, nuclear coordination of mitochondria, mRNA translation, and cell motility processes (33). In fact, the genes which code for coregulators appear to be the long sought master genes of Britten and Davidson (5), designed to coordinately control many diverse DNA-binding TFs to implement major physiological processes within the cell such as inflammation, fat and carbohydrate metabolism, and cell growth (3, 4, 5, 36). For purposes of this minireview, I define "master genes" as genes coding for coregulator molecules that can coordinately regulate subfunctions of many other TFs, in addition to cell processes such as translation, energy generation, and motility. For example, they are to be distinguished from rate-limiting master TFs of differentiation such as myoD in myocytes.

Important physiological regulators frequently are targets for pathologies, and the coregulators are no exception. There have been more than 285 of the coregulator molecules identified to date. This number would provide an enormous combinatorial potential for multitask regulation of the great number of genetic processes required in human physiology. Already, approximately 160 of the coregulators have been associated in publications with some pathological state (www.NURSA.org). The most frequent of the pathologies are a variety of cancers in which coregulators have been shown to serve as either oncogenes or tumor suppressors, depending upon signaling and cell context. Even with the recent explosion of information on coregulators over the past decade, I have the distinct impression that we are only viewing the tip of the iceberg of what remains to be learned for these fascinating master regulators.

	FOOTNOTES

 
First Published Online February 6, 2007

Abbreviations: CBP, CREB-binding protein; CREB, cAMP response element-binding protein; ERAP160, 160,000-Da estrogen-interacting protein; NR, nuclear receptor; Pol II, polymerase II; RIP140, receptor-interacting protein 140; SRC, steroid receptor coactivator; TAF, TBP-associated factor; TBP, TATA-binding protein; TF, transcription factor; TR, thyroid hormone receptor.

Received for publication January 9, 2007. Accepted for publication February 1, 2007.

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TOP ABSTRACT INTRODUCTION MASTER GENES? EARLY RELATED EXPERIMENTS EXPERIMENTS TOWARD COREGULATORS THE ERA OF COREGULATOR... MASTER GENES EXIST REFERENCES

 

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NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  LXRβ  |  LXRα  |  ERα

Coregulators:   P/CAF  |  CBP  |  SRC-1  |  ASC-2  |  NCOR  |  SMRT

Ligands:   T0901317

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