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Lives and Times of Nuclear Receptors

Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: Elaine T. Alarid, Ph.D., Department of Physiology, University of Wisconsin-Madison, 120 Service Memorial Institute, 1300 University Avenue, Madison, Wisconsin 53706. E-mail: alarid{at}physiology.wisc.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 
Down-regulation of receptor in response to ligand was one of the earliest functional readouts of steroid hormone action. The loss of total receptor content upon stimulation, referred to initially as receptor "processing," was carefully described with respect to receptor nuclear transformation or tight nuclear binding. It was these early studies that were the first to note a correlation between receptor turnover and induction of gene transcription, leading to the proposal that down-regulation of receptor was involved in mechanisms of transcriptional activation. This idea has now attracted renewed attention with the discovery that ligand-induced "processing" in the form of proteolysis is carried out by the 26S proteasome, a multicatalytic enzyme whose activity is directly coupled to cell-cycle control, signal transduction, and importantly, transcription. Here, we review our current understanding of the mechanism and relevance of proteolysis to receptor function based on general concepts that have emerged from analyses of liganded members of the nuclear receptor family.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 
RECEPTOR LEVELS IN cells are dynamic and are regulated primarily by the surrounding concentrations of their cognate ligands. The earliest descriptions of ligand regulation of receptor concentration were made by the groups of Jensen and Gorski, who reported that estrogen treatment resulted in a depletion of cytosolic estrogen receptor (ER) based on the decreased specific binding of radiolabeled 17ß-estradiol (1, 2). These studies were followed by characterization of receptor regulation in other steroid receptor model systems, and thus, it was established that the control of receptor by ligand is a conserved regulatory pathway. Initial characterization of receptor turnover was provided by the biochemical analysis of receptor levels in cytoplasmic and nuclear fractions. These studies were able to relate receptor processing to the extraction properties of the receptor and showed that receptor within nuclear fraction was the primary target for degradation (3, 4, 5, 6, 7). An important observation that was also made was the correlation between receptor processing and induction of gene transcription, which led to the hypothesis that down-regulation of receptor might be a component within the transcriptional activation mechanism (8). This notion, however, was controversial for several reasons. First, down-regulation is not a generalized response to ligand binding among nuclear receptors. Both androgen receptor (AR) and vitamin D receptor (VDR) are up-regulated by the addition of ligand, which demonstrates that down-regulation per se is not required for transcriptional activation (9, 10). Secondly, it was shown that nuclear receptors transcriptionally repress the expression of their own genes as part of a negative feedback loop (11, 12, 13, 14, 15, 16, 17). Based on this information, the loss of receptor could be explained as a consequence of transcription rather than an active participant. Today, the idea that receptor down-regulation may contribute to the transactivation mechanism is being revisited after the discovery that "processing," or proteolysis, of receptors is mediated through the ubiquitin-proteasome pathway. Pulse chase analyses illustrate that the turnover rates of many nuclear receptor proteins is controlled by ligand (Table 1), and inhibition of 26S proteasome activity prevents ligand-induced down-regulation of ER (18, 19, 20), progesterone receptor (PR) (21), glucocorticoid receptor (GR) (22), thyroid hormone receptor (TR) (23), retinoic acid receptor (RAR) (24), retinoid X receptor (RXR) (25), mineralocorticoid receptor26), and peroxisome proliferator-activated receptor (PPAR) (27). The general role of the proteasome in the regulation of receptor function is now being scrutinized in a number of studies that relate proteasome activity to various aspects of receptor biology.

	TARGETING LIGANDED RECEPTORS TO PROTEASOMES

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

Protein substrates that are destined for destruction by the 26S proteasome are typically marked by the covalent attachment of ubiquitin moieties. The specificity of the ubiquitination reaction is defined by the ability of the enzymatic machinery (E1 activating, E2 conjugating, and E3 ligating enzymes) to recognize and transfer ubiquitin to the protein to be degraded (reviewed in Ref. 43). Receptors that are degraded are thus distinguished by some property that allows them to recruit ubiquitination enzymes. A mutagenesis approach has been taken to identify sequence elements, or degrons, that are essential for ubiquitination and subsequent degradation of receptors. Analyses of various members of the family have revealed a conserved requirement for two domains in the control of receptor turnover that is generally applicable to all receptors in which it has been studied (27, 29, 30, 44). These two domains are the N-terminal B and C-terminal E domains that encode activation functions, AF-1 and AF-2, respectively. In this sense, nuclear receptors fall into a category similar to other transcription factors such as Myc, VP16, and E2F-1 in which the degron overlaps the transactivation domains (36, 45, 46). However, the distinction here is that neither AF-1 nor AF-2 is sufficient on its own. Both are essential and together constitute the elements required for recognition by the ubiquitination machinery. Direct and indirect interactions between AF-1 and AF-2 can occur in a ligand-dependent manner and are responsible for transcriptional synergy in certain contexts (47, 48, 49, 50, 51). Thus, one model for signaling degradation might involve ligand-facilitated interactions between the AF-1 and AF-2 that, when combined, create a binding surface for either a ligase or other accessory protein that is recognized by the ubiquitination machinery. This may provide one explanation for the increased transcriptional efficiency associated with proteolysis because it may relate to synergistic activities of AF-1 and AF-2. Alternatively, AF-1 and AF-2 may serve distinct purposes such as recognition vs. recruitment. The overall implication of the dual requirement for B and E domains is that, unlike transcription where AF-1 and AF-2 can function as independent modules, the signal(s) for ubiquitin/proteasome-mediated degradation are coordinated by distal regions of the receptor necessitating the full-length receptor.

The role of the C terminus in ligand-induced proteolysis is multifold. Most simply, the C terminus is required for ligand binding and induction of proteolysis. Ligands have variable effects on receptor proteolysis. For ER, multiple agonists induce degradation with a potency that is directly related to their binding affinity, although the efficiency of degradation can vary (52). For most receptors, partial agonists and antagonists fail to or only weakly induce proteolysis. Ligands including tamoxifen, RU486, and LGD100754 have been shown to stabilize ER, PR, and PPAR, respectively (27, 52, 53, 54). Exceptions to this rule are certain ER antagonists, such as GW5638 and ICI182780, which efficiently induce ER degradation (55). The general conclusion that can be made from agonist and antagonist studies is that the degradation signal is in part conferred by an active conformation in the ligand binding domain. This notion is further supported by mutagenesis studies of ER, PPAR, and RAR2, which show that point mutants within the AF-2 that disrupt transcription also stabilize receptor proteins both in the presence and absence of ligand (27, 29, 30). Thus, a second component of the proteolytic signaling mediated through the C terminus is likely a structural conformation induced by agonist binding that can be associated with a transcriptionally competent state.

Despite the importance of the receptor ligand binding domain, deletion of the N terminus renders receptors insensitive to ligand-induced degradation. This has been demonstrated for ER, RAR2, and PPAR (27, 29, 44). Deletion of the extreme N-terminal A domain does not impair degradation, pointing to the B domain and the AF-1 as the critical region. In contrast to AF-2, AF-1 is poorly defined and point mutants that selectively impair AF-1 function are lacking. However, AF-1 function can be modulated by phosphorylation induced by ligand binding or by growth factor-activated kinase cascades. The role of serine phosphorylation of AF-1 in signaling degradation of nuclear receptors has been demonstrated most clearly for PR and RAR2. In both models, steroid-induced phosphorylation of receptor is mediated through the MAPK cascade (21, 29, 56). Progestins stimulate p42/44 MAPK-mediated phosphorylation at S294 of PR, whereas retinoids induce p38-activated phosphorylation of S66/68 of RAR2. In both cases, loss of phosphorylation, either through selective inhibition of specific branches of the MAPK pathway or by mutation of serine to alanine, prevented ligand-induced down-regulation. These data support a model wherein phosphorylation is a positive signal for degradation.

Like the above examples, estrogen-induced degradation of ER is dependent on the N-terminal AF-1 domain. The primary target for ligand-induced phosphorylation of ER is S118 and mutation of this site results in loss of ER proteolysis, consistent with a possible role for phosphorylation in signaling receptor turnover. Calligé et al. (57) showed that the kinase inhibitor, curcumin, prevented estrogen-induced down-regulation of ER protein and correlated the decrease in receptor turnover with a loss of phosphorylation, although the site of phosphorylation was not defined. Other evidence, however, suggests that there is a greater complexity to the regulation of proteolysis mediated through this site. For instance, inhibition of proteasome activity does not preferentially spare the phospho-S118 form of liganded ER. Moreover, mutational substitutions of S118 that test the impact of phosphorylation-induced charge changes at this site (S118A and S118E) reveal differential regulation of ER proteolysis and transcription (44). Thus, this site can play multiple distinct roles in regulating ER activity. The phosphorylation at S118 itself remains a candidate in signaling ER degradation, but this has yet to be determined. Similar complexity in regulation is observed in the case of GR, where multiple phosphorylation sites in the B domain coordinate the regulation of GR protein stability (58).

Studies of kinase modulation of receptor degradation suggest that the overall stability of receptor protein may reflect a balance between ligand activation and the relative activities of kinases in the cell. A recent report surveyed the impact of a series of common pharmacological kinase inhibitors on ER degradation. Marsaud et al. (59) showed that protein kinase C increased proteolysis, whereas phosphatidylinositol-3-kinase increased stability. ERK7 can destabilize liganded ER protein, whereas activation of protein kinase A has the opposite effect (60, 61). These results suggest that the network of kinase activities may function like a rheostat that fine-tunes the ligand-regulated levels of receptor. They also point out that ligand regulation of receptor proteolysis is influenced by cell context-dependent mechanisms (see Table 1). Other examples of kinase-mediated control of receptor stability include the AKT-induced destabilization of AR and okadaic acid stabilization of TR (62, 63).

The contribution of the DNA binding domain has also been examined in an attempt to determine whether the early events in the transcriptional activation pathway mark receptors for degradation. Mutation analyses of DNA binding domains have yielded disparate results. In transient expression assays, disruption of the zinc-finger motif of ER and PPAR by point mutation did not impair ligand-induced degradation (27, 30) but deletion of the entire DNA binding domain abrogated proteolysis in the cases of ER and RAR2 (44, 55, 56). These differences serve as a reminder that disruption of the structural integrity of the protein can have consequences in the regulation mediated by this pathway. Although it remains undetermined whether DNA binding is a prerequisite for receptor degradation, chromatin immunoprecipitation analysis of ER suggests that DNA binding is not sufficient to target receptor to the ubiquitin proteasome pathway (44). Ligands, such as tamoxifen, promote recruitment of ER to promoters, yet stabilize receptor protein (50, 53). In addition, ER mutants resistant to proteolysis can be found bound to DNA (44). Interestingly, there is a correlation between the stability of ER and the ability of receptor to recruit E3 ligases, E6-associated protein (E6-AP) and mouse double minute 2 (MdM2), to target gene promoters (44). Thus, although DNA binding is not sufficient to target receptors for proteolysis, the stability of the receptor does relate to the recruitment of ubiquitination machinery to the DNA. Together, these data suggest that the signaling for receptor degradation involves events downstream of DNA binding and may include recruitment of ligases to active receptor transcriptional complexes.

	PROTEOLYSIS OF THE UNLIGANDED RECEPTOR

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 
The 26S proteasome plays a critical role in the removal of misfolded proteins in the cell. The destruction of imperfect proteins, or protein triage, is a priority of cellular metabolism, consuming as much as 11% of the ATP generated in some cells (64). The energy devoted to this pathway ensures against the formation of protein aggregates that compromise cellular viability. Protein triage by the proteasome represents one side of a delicate balance that is countered by heat shock proteins (hsp) that ensure proper protein folding (65). The wealth of knowledge of hsp regulation of nuclear receptor maturation has identified the receptors as useful models for dissecting the underlying mechanisms that control life and death decisions of nascent proteins.

Receptor association with hsp heterocomplexes is required to achieve ligand binding competency. The maturation process involves cycles of hsp binding and release as receptors adopt their native conformation (66). The hsp complex protects receptors by binding and shielding hydrophobic regions as the protein folds. Release of the client protein is triggered by ATP hydrolysis mediated through components of the hsp complex. During each of the release or exchange states, receptors are vulnerable to potential degradation as misfolded proteins. There are two major points in the chaperone assembly where receptors are particularly susceptible to proteolysis. The first event is the transfer of substrate from hsp40 to hsp70. ATP hydrolysis, triggered by hsp40, transfers protein substrate to hsp70 and promotes the association of hsp70 with a cochaperone, Hsc-70-interacting protein (Hip). Another cochaperone protein, BCL-2-associated athanogene-1 (BAG-1), can also bind to hsp70, displacing Hip as well as another cochaperone, Hsp organizing protein (Hop), from the heat shock complex (67, 68). BAG-1 and related polypeptides are ubiquitin-like proteins that can couple hsp70 and its client directly to the 26S proteasome. It has been proposed that BAG-1 may bring an hsp70 client within proximity of the proteasome and, through induction of nucleotide exchange, release substrate directly to the 26S proteasome for degradation.

Later in the maturation process, the ubiquitin-proteasome pathway challenges the folding machinery with the recruitment of carboxy-terminus of Hsc-70-interacting protein (CHIP), a U-box ligase. CHIP binds to hsp90 through a tetratricopeptide repeat domain and therefore competitively inhibits the binding of other tetratricopeptide repeat-containing cochaperones such as Hop and p23 (69). In disrupting hsp90 interactions with cochaperones, CHIP effectively alters the composition of the chaperone complex. Additionally, CHIP polyubiquitinates hsp-client proteins through its U-box domain, and can thus target them for proteolysis by the 26S proteasome.

Both CHIP and BAG-1 have been copurified with the unliganded ER along with hsp 40, hsp70, hsc70, and hsp90 (70). The function of BAG-1 is not well understood, but increased association with CHIP can increase the turnover rate of the unliganded ER and conversely, small interfering RNA against CHIP was shown to more than double the half-life of ER from 6 h to greater than 12 h (52). This increased association between receptor and CHIP can be pharmacologically induced by treatment with geldanamycin, an inhibitor of hsp90 ATP-binding activity (71, 72), which also destabilizes PR and GR (21, 73). Receptor disassociation from CHIP is induced by ligand binding. Thus, it appears that the 26S proteasome coregulates the maturation of the unliganded receptor along with hsp. The dynamics between proteolysis and chaperone activity likely underlie the establishment of steady state levels of functionally competent receptors.

	TARGETING PROTEASOMES TO RECEPTORS

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 
Defining the relationship between transactivator, proteasome, and control of transcription is an area that has exploded in the last few years. Studies of nuclear receptors have revealed multiple points of overlap between the proteasome and receptors. Components of the proteasome coexist with receptor and coactivators in nuclear-matrix-associated foci after ligand stimulation (74). Moreover, proteasome components are recruited to the DNA as part of the receptor-associated complex built on gene enhancers. Suppressor for Gal 1 (SUG1), a subunit of the regulatory 19S cap of the proteasome, directly interacts with a number of receptors and is recruited to ER-bound promoters with a delayed kinetics such that its recruitment overlaps with receptor release (31, 75, 76). The question remains whether SUG1 is a component of a proteolytic or nonproteolytic mechanism. Evidence supports both scenarios. SUG1 overexpression has been shown to influence ligand-induced degradation of RAR and ER in support of a proteolytic function (56, 77). In addition, SUG1 is recruited to promoters with a timing that is consistent with a role for proteasome in complex disassembly. Yet, SUG1 is recruited to ER bound promoters regardless of the stability of the receptor (44). Moreover, the periodicity of receptor DNA binding cycles does not appear to be affected by the stability of the receptor. The latter is shown by analysis of a stable ER isoform lacking the AB domain (ER:46), which cycles on and off the DNA with kinetics similar to wild-type receptor in the presence of estradiol (78). This evidence would suggest that ER proteolysis and SUG1 recruitment are independent events. In this context, the recruitment of SUG1 by ER may not contribute to receptor proteolysis but instead may serve to bring the 19S cap to sites of active transcription. A model put forth by the groups of Johnston and Kodadek (79, 80) proposes that the 19S cap plays a nonproteolytic function in the regulation of transcriptional elongation. In this model, ER activation would serve as a beacon that marks the transcriptionally active promoter to which SUG1 is recruited. SUG1 recruitment, along with elongation factors, would promote transcriptional elongation. Indeed, chromatin immunoprecipitation analysis has shown that SUG1 and elongation factors are simultaneously bound to the pS2 promoter (78). After elongation, the proteolytic component of the 26S proteasome would be recruited to remove stalled RNA polymerase II at the transcriptional stop sites terminating transcription (81). Further experimentation is necessary to test this model, but the preliminary information suggests that the nuclear receptors would be excellent model systems for such studies.

	MODULATION OF RECEPTOR FUNCTION THROUGH THE CONTROL OF PROTEOLYSIS

TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 
The degradation of receptors by the proteasome pathway has one functional endpoint—to eliminate receptors from the cell. Like cell surface receptors, the gross decline in receptor number is part of an adaptive response that allows cells to alter sensitivity to external stimuli depending on environmental conditions. Upon this centrally conserved pathway has been built a regulatory complexity that has broadened its functional role beyond the simple control of sensitivity to hormone. The events that target receptor for proteolysis provide entries into the pathway that can either be coupled or uncoupled to the control of transcription. Therefore, it is not so much the endpoint as it is the process by which receptors are identified for proteolysis that has shown to have the broadest impact on receptor activity.

Steady-state levels of receptor are controlled posttranscriptionally by the balance between hsp and cochaperones that promote proper folding or degradation of nascent proteins. The mechanisms responsible for partitioning receptors between these pathways are yet to be elucidated, but tilts in this balance have the potential to alter the availability of functional receptors. The impact of such changes in levels of unliganded receptor is demonstrated in overexpression studies of GR (82), PR (83), and ER (84, 85). At elevated levels, unliganded receptors bypass the requirement for ligand and become constitutively active. The hsp complex is traditionally considered to be the primary inhibitor maintaining the unliganded receptor in the inactive state. This paradigm can now be expanded to include proteolysis that, through the control of receptor availability, can function alongside hsp to maintain hormone-dependent regulation of steroid receptor transcription.

Proteolysis of receptors has also become a prominent cross-talk mechanism through which other pathways indirectly modulate receptor transcriptional activity. The targeting of liganded receptors to the 26S proteasome is regulated by elements in the B domain that overlap with modulation of receptor activity by kinase cascades. This allows for integration of receptor proteolysis with kinase modulation of receptor transcriptional activity. Several examples have shown that activated kinases can coordinately regulate receptor phosphorylation, degradation, and transcription. Shen et al. (32) showed that a constitutively activated MEKK1 both increases PR proteolysis and potentiates PR transactivation function. In the case of AR, AKT activation increases the turnover of AR, but the increased proteolysis is associated with an inhibition of AR-dependent transcription (62). Although there appears to be no generalized transcriptional response associated with an increase in proteolysis, it is clear that kinase-mediated cascades use the proteolysis pathway to indirectly modulate the transcriptional activity of steroid hormone receptors.

Cross-regulation of receptor function through modulation of proteolysis also occurs among members of the nuclear receptor family and other transcription factors. Examples include regulation of ER stability by TR, regulation of GR, AR, and VDR by ER, and regulation of heterodimer partners by RXR (33, 86, 87, 88). The mechanisms by which one receptor can regulate the stability of another are likely to be many and have not been fully explored. However, one mechanism for which some detail is available is receptor-mediated transcriptional regulation of E3 ligases. Estrogen activation of ER induces the expression of two ligases, MdM2 and Siah2. The estrogen-induced increase in MdM2 expression results in an increase in MdM2 protein concentration in the cytoplasmic compartment. Elevated cytoplasmic MdM2 protein increases its ligase activity directed at the GR. In this manner, ER accelerates the turnover of GR and concomitantly inhibits Dex-induced transcription. Because MdM2 is also implicated in the degradation of AR (62), it’s possible that similar mechanisms may explain estrogen-induced targeting of AR to the proteasome (88). In a separate example, ER regulation of Siah2 impacts nuclear receptor transcription, not through the control of receptor proteolysis, but through the control of corepressor degradation. Siah2 is an E3-ubiquitin ligase that interacts with nuclear receptor corepressor (NCoR) (89). Frasor et al. (90) demonstrated that increased expression of Siah2 induced by estrogen leads to a decrease in NCoR half-life, which in turn results in derepression of VDR-mediated transcription. Importantly, this pathway potentially impacts other transcription factors governed by NCoR including SP1, AP 1, NF-B, and Myc/Max. These examples illustrate that the proteolytic pathway provides a mechanism through which the transcriptional regulatory circuit of receptors can be expanded beyond the set of direct target genes.

Despite the tremendous progress that has been made in trying to understand ligand-induced degradation of receptor, the molecular events that specify receptor proteolysis are poorly defined. Several critical questions remain unanswered. For instance, the components of the ubiquitination machinery responsible for transferring ubiquitin to receptors and the sites of ubiquitination have not been definitively established. Several ubiquitin-conjugating enzymes and ubiquitin ligases have been implicated in the regulation of receptor transcriptional activity. Among the E2-conjugating enzymes, UBCH7 has been identified as a coactivator of the transcriptional activities of several steroid hormone receptors, including ER, PR, AR, GR, and RAR (91). Characterization of UBCH7 activity in receptor-mediated transcription suggests that the UBCH7 does not directly interact with receptors but instead interfaces with receptor transcriptional complexes through direct interactions with the p160 coactivator, steroid receptor coactivator 1. Like UBCH7, many E3 ligases have also been shown to influence ligand-dependent nuclear receptor activity. These include HECT domain-containing ligases such as E6-AP and Rsp5/Rpf1 (92, 93), and RING finger ligases, MdM2, BRCA1, and RNF8, which can function as transcriptional coactivators or are found in transcriptional complexes on promoters (31, 62, 87). Despite the identification of these ubiquitination enzymes as modulators of receptor transcriptional function, their activity in relation to ubiquitination and proteolysis of receptors has yet to been determined. This is in part due to technical difficulties in detecting ubiquitinated intermediates, but it also emphasizes the need for increased biochemical analysis of receptor proteolysis.

Receptors function in a dynamic environment. They associate with chromatin in a time frame of seconds, are highly mobile within the nucleus and cytoplasm, and build transcriptional complexes in pulses of DNA-binding activity. As a consequence, receptors cannot be viewed as homogeneous population. They exist in different places, in different complexes, with different functions, at different times. Which of these receptor populations are targets for proteolysis? Is proteolysis regulated through receptor localization? Does proteolysis of receptor dictate the fate of other proteins with which receptor is associated? Is proteolysis of receptor the termination signal for transcription? In the broader context, it will be important to understand the relevance of receptor proteolysis in endocrine-related pathologies and its potential therapeutic applications. As shown in Fig. 1, the 26S proteasome looms large at multiple stages within the life of nuclear receptors. It is present in the beginning where the intimate association with hsp chaperones allows the proteasome to regulate the availability and activity of unliganded receptor. With regard to the activated receptor, the proteasome can play both proteolytic and nonproteolytic roles in the transcriptional pathway. In its proteolytic function, the 26S proteasome degrades multiple components of the transcriptional complex including receptor, coactivators, RNA polymerase II (Pol II), among others. In a nonproteolytic role, the 19S regulatory cap engages the elongation machinery. The 26S proteasome-mediated degradation of receptor represents the end stage of the life cycle where inactive receptors, whether aged through the transcriptional process or having never arrived at its transcriptional target, are cleared from the cell. The potential links between receptor function and proteasome-mediated proteolysis are extensive, and future experimentation in this area promises to touch upon fundamental issues in transcription as well as receptor biology.

View larger version (86K): [in this window] [in a new window]   Fig. 1. Model of Nuclear Receptor Life-Cycle with Respect to Receptor Protein Regulation by the 26S Proteasome During the folding of the nascent protein, receptors (R) encounter an assembly of hsp, cochaperones (Hip, Hop), and immunophilins (Im) that cycle between bound and release states as receptors progress toward maturation. The cochaperones, BAG-1 and CHIP, compete with other cochaperone proteins and can interact directly with the 26S proteasome to capture misfolded receptors and target them for degradation. Ligand-binding releases receptor from hsp heterocomplexes and induces the posttranslational modifications that drive receptor to nucleate complexes consisting of histone methyltransferase (HMT), histone acetyltransferases (HAT), coactivators (CoA), ubiquitin ligases (E3), mediator complex (Med), and RNA polymerase II (Pol II) that actively engage in transcription. Alternatively, ligand-activated receptor complexes can be directly targeted for degradation by the 26S proteasome. The 26S proteasome regulates receptor transcriptional function through the regulated destruction of multiple components of the transcriptional apparatus, including receptors (R), coactivators (CoA), corepressors (CoR), and RNA polymerase II (Pol II). Additionally, the 19S regulatory subunit of the proteasome, SUG-1 (SUG) is implicated in the regulation of both transcription initiation and elongation. SUG1 and elongation factors (Elongator) are recruited to receptor-bound promoters during complex disassembly. It has been suggested that the 19S proteasome plays a proteolytic role in promoter clearance and a nonproteolytic role in transcriptional elongation. At the end of the receptor life cycle, "spent" receptors and their homo- or heterodimeric partners encounter the 26S proteasome for ultimate destruction. The complex overlap between the signals that target receptor for proteolysis and for transcriptional activation is used in various cross talk mechanisms that allow nuclear receptors to interface with growth factor signal transduction cascades as well as other transcription factors. See text for details.

	ACKNOWLEDGMENTS

 
I express thanks to those many laboratories who have contributed to our understanding of receptor proteolysis and apologize to those whose work I did not include. Thanks also go to Chris Valley and Stephanie Ellison for editorial assistance.

	FOOTNOTES

 
This work was supported by National Institutes of Health Grant DK64034.

E.T.A. has no disclosures to declare.

First Published Online January 19, 2006

Abbreviations: AF, Activation function; AP-1, activator protein 1; AR, androgen receptor; BAG-1, BCL-2-associated athanogene-1; BCL, B-cell leukemia/lymphoma; CHIP, carboxy-terminus of Hsc-70-interacting protein; E6-AP, E6-associated protein; ER, estrogen receptor; GC, glucocorticoid receptor; HECT, homologous to E6-AP carboxyl terminus; Hip, Hsc-70-interacting protein; Hop, Hsp organizing protein; Hsc, heat shock protein cognate; hsp, heat shock protein(s); MdM2, mouse double minute 2; NCoR, nuclear receptor corepressor; NFB, nuclear factor B; PPAR, peroxisome proliferator-activated receptor; PR, progesterone receptor; RAR, retinoic acid receptor; RING, really interesting new gene; RXR, retinoid X receptor; SUG1, suppressor for Gal 1; TR, thyroid hormone receptor; VDR, vitamin D receptor; VP16, viral protein 16.

Received for publication November 29, 2005. Accepted for publication January 11, 2006.

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TOP ABSTRACT INTRODUCTION TARGETING LIGANDED RECEPTORS TO... PROTEOLYSIS OF THE UNLIGANDED... TARGETING PROTEASOMES TO... MODULATION OF RECEPTOR FUNCTION... REFERENCES

 

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Nuclear Receptors:   TRα  |  RARα  |  PPARα  |  PPARγ  |  VDR  |  ERα  |  GR  |  MR  |  PR  |  AR

Coregulators:   TRIP1  |  E6AP  |  UBCH7  |  BAG-1  |  BRCA1  |  SRC-1  |  NCOR  |  RPF1

Ligands:   17β-Estradiol  |  RU486

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