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Urban Renewal in the Nucleus: Is Protein Turnover by Proteasomes Absolutely Required for Nuclear Receptor-Regulated Transcription?

Cancer Center (Z.N.), Creighton University, Omaha, Nebraska 68178; and Department of Molecular and Cellular Biology (B.W.O.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Bert W. O’Malley, M.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: berto{at}bcm.tmc.edu.

	ABSTRACT

TOP ABSTRACT REFERENCES

 
The importance of the ubiquitin proteasome pathway in higher eukaryotes has been well established in cell cycle regulation, signal transduction, and cell differentiation, but has only recently been linked to nuclear hormone receptor-regulated gene transcription. Characterization of a number of ubiquitin proteasome pathway enzymes as coactivators and observations that several nuclear receptors are ubiquitinated and degraded in the course of their nuclear activities provide evidence that ubiquitin proteasome-mediated protein degradation plays an integral role in eukaryotic transcription. In addition to receptors, studies have revealed that coactivators are ubiquitinated and degraded via the proteasome. The notion that the ubiquitin proteasome pathway is involved in gene transcription is further strengthened by the fact that ubiquitin proteasome pathway enzymes are recruited to the promoters of target genes and that proteasome-dependent degradation of nuclear receptors is required for efficient transcriptional activity. These findings suggest that protein degradation is coupled with nuclear receptor coactivation activity. It is possible that the ubiquitin proteasome pathway modulates transcription by promoting remodeling and turnover of the nuclear receptor-transcription complex. In this review, we discus the possible role of the ubiquitin proteasome pathway in nuclear hormone receptor-regulated gene transcription.

THE DISCOVERY OF coactivators for nuclear receptors has led to the identification of a number of molecules that contain both a coactivation function as well as an enzyme activity. That coactivators have activation domains for regulating transcription would be expected, but the inclusion of enzymatic activities was less obvious when considering their role in transcription. Histone acetyl transferase (HAT) activity was the first enzymatic function implicated in nuclear hormone receptor-dependent transcription (1, 2, 3, 4) followed by a coactivator with ubiquitin-protein ligase activity (5). Identification of a number of ubiquitin pathway enzymes as coactivators implicated another type of enzymatic activity as being a component of nuclear receptor function and provided evidence that ubiquitin proteasome-mediated protein degradation could play an integral part in eukaryotic transcription (6). Subsequently, histone methyl transferase (HMT) and ATPase activities also were linked to hormone receptor-dependent gene transcription (7, 8, 9, 10).

HAT activity was first recognized in the yeast transcriptional modulator, GCN5 (11), and was later shown to be a concomitant of multiple nuclear coactivators in mammals, including p300/CREB-binding protein-associated factor, CBP (CREB-binding protein), SRC-1 (steroid receptor coactivator-1), and activator of thyroid and retinoic acid receptors (1, 3, 12, 13). This enzymatic function was shown to act on histone substrates, acetylating their N-terminal lysine residues, thereby weakening the interactions with the negatively charged DNA and resulting in altered nucleosome or DNA structure near the target promoters (14). Evidence has accumulated for such a theory, although much of it is correlative. Although histones remain the most likely targets for acetylation, other transcription factors, including p53 and certain nuclear receptors such as androgen receptor and estrogen receptor (ER), also have been shown to be acetylated (15, 16, 17, 18). In the case of p53, acetylation increases binding to specific DNA sequences, whereas acetylation of receptors may increase their sensitivity to ligand-induced transactivation and corepressor disengagement (15, 16, 17, 18). Coactivators themselves are also targets of acetylation by other coactivators, the full reasons for which remain unclear (4). In addition to HAT activity, the multiprotein coactivator-containing "coregulatorsome complexes" also contain ATPase and HMT activities. The ATPase activity is a requisite to physically open the local repressive chromatin structure to allow easier access to DNA for other ancillary transcription proteins. Despite the fact that histones are major targets of HMT activity, it is likely that coregulators and other proteins in the coregulatorsome complex, such as CBP, are targets of methylation (19).

Another group of coactivators for nuclear receptors that have been shown to have enzymatic activities are the E3 ubiquitin-protein ligases that include E6-associated protein (E6-AP) and hRPF1/RSP5 (5, 20). The E6-AP protein is capable of associating with the human papillomaviruses type 16 and 18 E6 proteins; these complexes, in turn, led to degradation of p53 (21). However, during a search for nuclear receptor-associated regulator proteins by yeast two-hybrid screening, E6-AP was found to have general coactivation activity for nuclear receptors with a preference for steroid receptors (5). As per the usual paradigm, the E6-AP molecule had transcriptional activation domains thought to touch other coregulators or general transcription factors, and it also had enzymatic ubiquitin-protein ligase activity. Mutation of a critical cysteine in the hect domain responsible for ubiquitinating substrates did not abolish the receptor coactivation function, indicating that the hect domain plays only a structural and not enzymatic role (5).

The coupling of nuclear receptor coactivation activity with enzymatic protein degradation activity was puzzling. Why carry an enzyme into the transcription complex that would promote 26S proteasome activity and transcription factor degradation? Initially, it seemed contradictory because biochemists, for years, have done all that was possible to minimize or prevent degradation of biologically important proteins. It was a bit less surprising when another ubiquitin pathway enzyme, UbcH7, was shown to bind to activated receptors and enhance their transcriptional functions (Nawaz, Z., manuscript in preparation) (22). The enzymatic activity of UbcH7 was required for its ability to potentiate transactivation by steroid receptors, and UbcH7 was recruited to the target promoter in a hormone-dependent manner. Furthermore, the E3 ubiquitin ligase E6-AP and components of the regulatory subunit of the proteasome (Rpt6 and S1) are recruited to the hormone-responsive promoter. E6-AP, Rpt6, and S1 have been reported to be associated cyclically with the target promoter, which can occur in either the absence or presence of ligand (23, 24). Enzymes of the ubiquitin-like pathways, small ubiquitin related modifier 1 and neural precursor cell expressed, developmentally down-regulated 8, are also tied to the steroid hormone receptor activation pathway (25, 26, 27, 28, 29). The obvious conclusion was that these enzyme activities were important for some unsuspected aspect of nuclear receptor function at the level of DNA transcription.

The plot was thickened by a series of subsequent observations. It was observed that several nuclear receptors such as ER, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoid X receptor, and retinoic acid receptor (RAR) were ubiquitinated and degraded in the course of their nuclear activities (6, 30, 31, 32, 33, 34, 35, 36, 37). What could be the signal for receptor degradation? The ER, PR, vitamin D receptor, RAR, and TR undergo minor degradation in the absence of hormone, most likely due to unstable interactions within inactive chaperone-nuclear receptor complexes. However, enhanced cell-dependent degradation occurs once receptor binds to hormone (6, 30, 33, 34, 35, 36, 37). Hormone binding itself could be a signal for degradation, but evidence suggests that other activating events are involved. For instance, nuclear receptors undergo acetylation and multiple phosphorylation events after activation by hormone (15, 16, 38). Mutation of MAPK phosphorylation sites in PR and acetylation sites in ER reduced hormone-dependent degradation, suggesting that phosphorylation and acetylation of nuclear receptors may influence degradation (16, 36). Coactivators directly bind to nuclear receptors through helix-12, and specific amino acids have been identified within the helix-12 of ER and RAR that are indispensable for interaction with coactivators (33, 39, 40, 41). Mutations of these residues prevent hormone-dependent degradation, suggesting that coactivator binding could also be a possible signal for degradation (33, 40). Recently, it has been demonstrated that cross-talk among different receptors can influence receptor degradation. ER modulates protein levels of GR via the ubiquitin-proteasome pathway by regulating the expression levels of ubiquitin-proteasome pathway enzymes. ER regulates protein levels of GR by increasing expression levels of an E3 ubiquitin ligase, murine double minute 2, that is thought to then promote GR degradation by the ubiquitin-proteasome pathway (42). Although evidence suggests that multiple degradation signals exist, further research will be needed to determine whether cross-talk, coactivator binding, phosphorylation, and other events contribute to receptor degradation independently, or whether they are all part of an interconnected mechanism to promote receptor turnover.

In addition to the nuclear receptors, recent studies also revealed that corepressors and a number of SRC family coactivators, CBP and E6-AP, are ubiquitinated and specific sets of ubiquitin pathway enzymes promote ubiquitination of specific coactivators (40, 43). Furthermore, ubiquitination also occurs concomitant with other transcription factor activities, and it has been suggested that ubiquitination of transcription factors also might be required to activate them for transcription (44, 45, 46, 47). RNA polymerase itself is ubiquitinated, and the TAF_II250 subunit of the polymerase II general initiation factor IID, has been shown to possess ubiquitination activity (48, 49, 50). Finally, stability of mRNA may be modulated by the ubiquitin-proteasome pathway (51, 52).

The facts suggest that under select conditions, multiple nuclear receptors are degraded concomitantly with transcriptional activation induced by these same receptors. In fact, the addition of the 26S proteasome inhibitors MG132 and lactacystin were inhibitory to nuclear receptor function, indicating that the prevention of degradation may be deleterious to regulation of transcription by certain receptors (40). The addition of excess coactivators does not overcome this drug-induced repression of transcription. The notion that the ubiquitin proteasome pathway is involved in gene transcription is further strengthened by the fact that 26S proteasomes are present in the mammalian nucleus (53) and that ubiquitin-proteasome pathway enzymes are recruited to the promoters of target genes (25).

Recently, it has been shown that steroid hormone receptors (ER and androgen receptor) and their coactivators cycle onto and off steroid-responsive promoters in a hormone-dependent manner (24, 25, 54). Steroid receptors, coactivators, and polymerase II are recruited to target promoters within 15–30 min after the addition of hormone. Receptor promoter occupancy peaks at 30–45 min and returns to baseline by 75 min. The second cycle of promoter occupancy starts at about 100 min after hormone treatment. These cycles of assembly of steroid hormone receptor complexes are followed by transcription of target genes (24, 54). It is conceivable that the ubiquitin proteasome pathway may be involved in the cycling of receptors and coactivator complexes. This notion is supported by the most recently published studies, which demonstrate that ubiquitin proteasome activity is required for the cycling of steroid hormone receptors on hormone-responsive promoters (24). Moreover, proteasome-dependent degradation of steroid receptor requires transcriptional activity, suggesting that degradation and receptor transactivation are mutually interdependent (25). It has been suggested that receptor degradation does not occur directly on the target promoter and that the nuclear matrix plays an essential role in the degradation of receptor. The nuclear matrix may provide a scaffolding role in the movement of the ubiquitinated receptor to the proteasome-active sites (25). In addition to receptor and coactivator cycling, the E3 ubiquitin ligases and the components of the regulatory subunit of the proteasome also cycle on hormone-responsive promoters (24, 25, 54). The cyclic association of receptors, E3 ligases, and the components of the proteasome with hormone-responsive promoters may be a mechanism to acutely respond to the changes in the concentration of circulating hormone and exert tighter control over gene expression. It is possible that proteasome function contributes to gene transcription by disrupting the preinitiation complex, allowing elongation to proceed. It also is plausible that the proteasome pathway is required to exchange coactivator complexes for transcription initiation, elongation, and RNA processing. These possibilities are supported by observations that show accumulation of 26S proteasomes (or subunits) at sites of nuclear receptor-induced gene activity (55). When taken together, the available data suggest that proteasome activity is a necessary concomitant of regulated gene activity.

In the pathway for ubiquitinylation of coregulatorsomes, there appears to be a very limited number of E1-activating enzymes and a moderate number of E2-conjugating enzymes. In contrast, there are more than 50 E3 ligases described to date. It is thought that the E3 ligases may have substrate specificities. Also interesting is the fact that a number of E3 ligases have been reported in the literature to be nuclear receptor coactivators. We are currently studying three additional new E3 enzymes that are present in high-molecular weight complexes of coactivators (O’Malley, B. W., unpublished data). It may be that the large number of associated E3s point to substrate specificity for distinct coactivator (and corepressor) complexes subjected to 26S proteasome degradation.

The concept of an obligate turnover of transcription factors can be supported by a consideration of the structure of receptor induced by ligand. Using proteolytic digestion mapping and monoclonal epitope mapping, we postulated that the C-terminal tail of the steroid receptor, now referred to as helix 12 after crystallization of the receptors, was in an extended conformation when complexed with antagonists (or unoccupied by ligand) (56, 57, 58). This made functional sense to us because, in separate studies, we predicted that the C-terminal tail of receptors was inhibitory to function and led to a repressed state of activity (59, 60). Indeed, crystal structures of agonist-occupied receptors revealed that the ligand was buried deep within a ligand pocket and that the C-terminal region (helix 12) indeed covered the ligand within the receptor molecule. Furthermore, a coactivator (e.g. SRC-1) makes additional contacts over the surface above the ligand pocket also touching helices 3, 5, and 11 (61, 62). This model generated a conundrum as to how the ligand ever escapes its molecular prison? And if it does not escape, how does hormone-induced transcription cease? If there is one axiom accepted by most endocrinologists, it is that the response of endocrine target tissues to hormone is tightly regulated and transient, and is dependent upon continued circulating levels of available hormonal ligand. Nevertheless, this occurs under conditions in which the receptor locks the hormone within its activation pocket and covers the pocket with coactivators.

Recent evidence revealed a striking change in the dissociation rate of estradiol from its receptor in the presence of even fragments of SRC-1 bound to the agonist-occupied ligand-binding domain of the ER (63). It can be predicted that the dissociation rate would be slowed even more if full-length SRC-1 were employed in the studies, due to additional contact points for SRC-1 on the receptor (64). To make matters worse, assembling what appears to be a complex of additional multiple coactivators on top of this receptor-SRC-1 complex could provoke a semipermanent driving force for target gene expression. Thus, there would appear to be no room to evoke breathing of helix 12 as a mechanism for escape of ligand; and certainly, the receptor itself is incapable of degrading the hormone.

We believe there are only a limited number of possible solutions to this problem. For one, an immense source of energy may be delivered directly to the receptor-coregulator complex, which would lead to conformational reversal, coregulator dispersal, and hormone dissociation. Another explanation would be that the large number of enzymes that accumulate on the receptor bound at the DNA hormone response site lead to modifications of proteins within the complex, thereby weakening contact points and aiding in dissociation and perhaps revitalization of the regulatory proteins (Fig. 1). Although the above mechanisms may play a role in turnover, why ignore the accumulated data described above, most of which is consistent with degradation via a 26S proteasome mechanism?

View larger version (34K): [in this window] [in a new window]   Fig. 1. Postulated Mechanisms for Coactivator-Regulated Turnover of the Nuclear Receptor-Transcription Complex In the absence of hormone, nuclear receptors undergo a basal amount of degradation; however, in most cases enhanced receptor degradation occurs once receptor binds to hormone. In the presence of hormone (H), steroid receptors (Rc) undergo conformational changes that result in release of negative regulators and recruitment of coactivator complexes, general transcription factors (GTF), and polymerase II (Pol. II) to target promoters. The negative regulators are cleared from the cell via the ubiquitin-proteasome pathway. To activate transcription, hormone-bound receptor recruits ubiquitin-proteasome pathway enzymes; E6-associated protein (E6-AP) and ubiquitin-conjugation enzyme 7 (UBCH7) are examples of coactivators that are recruited to the promoter of target genes and which then modulate transcription by promoting complex remodeling and turnover of the nuclear receptor-transcription complex via the ubiquitin-proteasome pathway. Ubiquitin-proteasome-dependent degradation and receptor-dependent transactivation are linked and act continuously to degrade the ligand-bound receptor through the ubiquitin-proteasome pathway to maintain efficient transcription of the target promoter gene. In order for eventual down-regulation of the transcriptionally active nuclear receptor, coactivator complexes, and Pol. II, the ubiquitin-proteasome pathway is important again for removal of the active complexes from the target promoter.

Therefore, we are left with a number of scenarios for transcriptional regulation via receptor-coregulatorsome degradation. First, it is a mechanism by which transcription can be ended in a satisfactory period to account, at least in part, for the in vivo hormonal kinetics. This would imply significant degradation of nuclear/steroid receptors as well as their attendant coregulatory (coactivator/corepressor) proteins. This hypothesis is not incompatible with a certain amount of recycling and reutilization of members of the complex, a reaction that is beyond the scope of this commentary (65, 66, 67). There is good evidence that energy may be required for entry of certain receptors into the nuclear compartment and that recycling of certain receptors occurs, especially in the case of glucocorticoid action (68, 69, 70).

A more radical hypothesis, however, would suggest that turnover of the receptor-coregulatorsome complex would occur in a rapid and continuous fashion, each new complex requiring sufficient concentrations of hormonal ligand to occupy receptor, an adequate supply of receptor (or newly synthesized receptor), and sufficient coregulator concentrations to maintain adequate target gene expression in the face of the appropriate hormone levels. For this to occur, one does not need to predict vast excesses of coactivators or extremely high rates of synthesis of these molecules. In fact, down-regulation or desensitizing actions are a sine qua non of the endocrine system and serve as an important contradictory influence for cellular overstimulation by hormones. As a concomitant of this hypothesis, turnover of the receptor-coactivator-initiation complex may be required for transition to the receptor-coactivator-elongation complex, the receptor-coactivator-splicing complex, or subsequent complexes operative at other downstream steps of gene expression. As is usual in biology, some combination of the above scenarios is likely to be the case. Although kinetic experiments and additional data are required before acceptance of the hypothesis that turnover is an absolute prerequisite for efficient and appropriately regulated movement of receptor-coactivator complexes through the multiple stages of transcription, you can bet on proteasome-mediated turnover as playing a significant role in nuclear receptor and coregulator function in mammals.

	ACKNOWLEDGMENTS

 
We thank David Lonard for critical review of this manuscript.

	FOOTNOTES

 
This work was supported in part by NIH Grant DK56833, Nebraska State Grants LB595 and LB692 (to Z.N.), and NICHD, Welch Foundation, and Atlas Consortium grants (to B.W.O.).

Abbreviations: CBP, CREB-binding protein; E6-AP, E6-associated protein; ER, estrogen receptor; GR, glucocorticoid receptor; HAT, histone acetyl transferase; HMT, histone methyl transferase; PR, progesterone receptor; RAR, retinoic acid receptor; SRC, steroid receptor coactivator; TR, thyroid hormone receptor.

Received for publication October 6, 2003. Accepted for publication November 11, 2003.

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