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associates with Hsc70
1 The Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
2 Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
3 Department of Obstetrics and Gynecology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan
4 ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
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Abstract |
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is maintained silent in gene regulation upon the target gene promoters, we biochemically searched interactants for hER, and identified heat shock protein 70 (Hsc70). Hsc70 appeared to associate with the N-terminal hormone binding E domain, that also turned out a transcriptionally repressive domain. Competitive association of Hsc70 with a best known coactivator p300 was observed. Thus, these findings suggest that Hsc70 associates with unliganded hER, and thereby deters hER from recruiting transcriptional coregulators, presumably as a component of chaperone complexes. |
Introduction |
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and ß, belong to the nuclear receptor superfamily and act as ligand-induced transcription factors. Like in other nuclear receptor superfamily members, structure of the ER proteins is divided into five or six functional domains (designated as A to E/F domains) (Mangelsdorf et al. 1995). The highly conserved DNA binding domain is located in the C domain, while the ligand-binding domain (LBD) is mapped to the E/F domain. Ligand binding causes a conformational change with dramatic shifting of the helix 12. In the ER, transactivation function is present in the N-terminal A/B domain (AF-1) and in the C-terminal LBD (AF-2) (Kumar et al. 1987; Tora et al. 1989). Although both AF-1 and AF-2 are involved in the ligand-dependent transactivation function of the ER, AF-1 is constitutively active, while AF-2 activity is dependent on the ligand binding (Endoh et al. 1999; Kobayashi et al. 2000; Watanabe et al. 2001). ER target gene promoters contain estrogen response elements (EREs) that are recognized and directly bound by ER homo- or hetero-dimers followed by chromatin remodeling, presumably by recruited ATP-dependent chromatin remodeling complexes (Belandia & Parker 2003; Kitagawa et al. 2003). ERE bound liganded ERs also recruit a number of histone acetyltransferases (HATs) and non-HAT cofactors that further enhance transcription (McKenna & O'Malley 2002). HAT coactivator complexes, CBP/p160 (Onate et al. 1995; Kamei et al. 1996; Chen et al. 1997; Spencer et al. 1997) and TRRAP/GCN5 (Yanagisawa et al. 2002), and non-HAT DRIP/TRAP complexes (Fondell et al. 1996; Yuan et al. 1998; Naar et al. 1999; Rachez et al. 1999) are thought to act as common coactivator complexes for ERs as well as for other DNA-binding transcription factors. Thus, ligand-induced conformational alteration switches ER from transcriptionally suppressed into transcriptionally active state via the recruitment of coactivators (Freedman 1999; Glass & Rosenfeld 2000; Metivier et al. 2003). Despite identification of a large number of factors/complexes that coactivate the ER function, a factor/complex that associates with unliganded ERs and suppresses their transactivation function remains to be identified. Although several HDAC complexes containing NCoR/SMART or sin3A (Kurokawa et al. 1995; Nagy et al. 1997) have been reported to be recruited by synthetic estrogen antagonist-bound ERs (Jepsen et al. 2000; Yamamoto et al. 2001), HDAC complexes are unlikely to render unliganded ERs suppressive in gene regulations even though unliganded ERs are bound to EREs, since unliganded ERs are unable to suppress the basal activity of the target gene promoters. Considering recent findings that eight classes of nuclear complexes are differentially and temporally recruited to ERE bound ERs (Metivier et al. 2003), it is feasible that unliganded ERs also associate with some cytosolic and/or nuclear factors/complexes.
To address this issue, this study has been undertaken to identify an ER interactant that renders ER inactive in transactivation. As unliganded ER is transcriptionally inactive, first we have mapped a molecular region in its structure that is involved in suppression of the basal transcriptional activity of the wild-type ER. A segment in the ER LBD N-terminal region has been identified as repression domain (ER RD). To search for proteins interacting with unliganded ER, we used HeLa cell nuclear extract that is known to contain major, if not all, coactivator complexes to support the transactivation function of the liganded ER. Using some of the modern biochemical techniques, we have identified heat shock protein 70 (Hsc70) as a factor that physically associates with the ER RD in vivo and in vitro. Thus, the present study indicates that a chaperone complex containing Hsc70 associates with the unliganded ER, thereby prevents ER from recruitment of coactivators and renders the receptor transcriptionally silent.
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Results |
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Human estrogen receptors (hERs) are well known to be transcriptionally silent when ligand is unbound irrespective of DNA binding. Although other members of nuclear receptor superfamily, like retinoid receptors (RAR/RXR) and thyroid hormone receptor (TR), are potent repressors of basal transcriptional activity of the target promoters in the absence of cognate ligands (Kurokawa et al. 1995; Nagy et al. 1997), unliganded ERs are shown not to exhibit such suppressive function. It is, therefore, most likely that unliganded ERs associate with transcriptionally neutral factors, that attenuate the transactivation function of the N- and C-terminal domains (AF-1 and AF-2) of ERs.
To test this hypothesis, we first mapped a transrepressive region in the human ER using a series of hER deletion mutants (Fig. 1A) in a transient expression assay in HeLa cells with a luciferase reporter gene harboring consensus ERE in the promoter. As expected from the previous findings that the N-terminal AF-1 domain is ligand-independent in transactivation, the mutants lacking the LBD [ER(1-288)] were active in transcription (Fig. 1B). The AF-2 function in the LBD appeared intact to confer estrogen responsiveness in the mutants retaining the LBD (Fig. 1B). The D domain itself appeared to have no transactivation function; however, the vicinal LBD region (340-396 amino acids) was rather suppressive for the AF-1 function (Fig. 1B). Together with a further C-terminal extention (396-461 a.a.), these two regions together (340-461 a.a.) appeared to act as a repression domain for the AF-1 domain. We therefore addressed this possibility by deleting only these regions (see ER(
341-396) and ER(341-461)) and indeed, found that only the mutant lacking of both regions acquired ligand-independent transactivation function, clearly confirming that the region between 341 and 461 a.a. (designated as hER Repression Domain) is capable of inhibiting the hER AF-1 function in the A/B domain. To verify the AF-1 function in the hER (341-461) mutant, transcriptional effect of the p300 HAT coactivator on this mutant was examined (Fig. 1C). p300 has been already reported to coactivate both AF-1 and AF-2 functions (Kobayashi et al. 2000; Watanabe et al. 2001), and consistently it potentiated the transactivation function of the tested hER mutants. Thus, even though the ligand is unbound, the AF-1 A/B domain is apparently exposed for recruitment of coactivators like p300 when the RD domain is deleted from the hER.
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To address the question of whether the RD domain harbors a transrepressive function or alters hER secondary structure to render the receptor inactive in transactivation, the function of the RD was examined in the mammalian two-hybrid system assay using GAL4 DNA binding domain-fused chimeric hER mutants and transcriptional activator VP16 fusion constructs (Fig. 2). The AF-1 function of the hER deletion mutant [ER(1-461)] is inactive due to the presence of RD domain, and GAL4-VP16 expectedly had no effect on the transactivation of this hER mutant. However, when GAL4-VP16 was fused with the RD domain [GAL4-VP16-ER(341-461)], this fusion protein was capable of stimulating transcriptional activity of hER(1-461), suggesting that the RD domain fused to GAL4-VP16 fusion protein quashes the RD function (Fig. 2). Considering that even a most potent activator, VP16, by itself did not interfere with the transactivation function of hER(1-340) by competing with the recruitment of coactivators, it is most likely that the RD domain associates with a transcriptionally neutral protein factor.
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To identify an unliganded ER RD-interacting protein(s), we have undertaken a biochemical approach to purify from HeLa nuclear extract factors and complexes associating with the hER (Fig. 3A). As we have previously reported, a number of factors like TFTC-type HAT complex components were trapped by the hER only in the presence of E2 (Yanagisawa et al. 2002), confirming our purification of ligand-dependent interactants (Fig. 3A). Only a few proteins bound to unliganded hER were detected, and one of them was identified by TOF-MS as heat shock protein p70 (Hsc70) (Ballinger et al. 1999; Alberti et al. 2002) that was undetectable in fractions purified with liganded hER (Fig. 3B). To verify the Hsc70 association with unliganded hER, co-immunoprecipitation was performed from HeLa cells (Fig. 4). Endogenous Hsc70 was co-immunoprecipitated with hER only when the cells were untreated with E2 (Fig. 4A). Furthermore, Hsc70 association with hER required RD domain (Fig. 4B). Thus, these findings suggest that Hsc70 dissociates from hER upon estrogen binding, releasing hER from its suppressive action.
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transactivation function through the RD domain is a nuclear event
To exclude the possibility that the transrepressive function of the RD domain towards the AF-1 and AF-2 is coupled with simply an extranuclear event, cellular localization of the hER mutants was examined (Fig. 5). As expected from the previous reports, wild-type hER mainly localized in the nuclei irrespective of E2 binding, and partial cytoplasmic localization of hER indicated the intracellular shuffling (Watanabe et al. 2001). In accordance with the previous findings that, similar to other nuclear receptors, major nuclear localization signal (NLS) is present in the hER hinge D domain (256-303 a.a.) (Ylikomi et al. 1992), all of the tested mutants retaining the D domain were predominantly localized in the nucleus, and the hER(341-461) mutant was indistinguishable from the wild-type hER in intracellular localization. Hsc70 localization was monitored as a GFP fusion protein, and was located mainly in the cytoplasm. However, in the presence of unliganded hER and hER mutants retaining the RD, albeit as a weak signal, nuclear localization of Hsc70 has also been detected (Fig. 5). Thus, from these findings it is apparent that the function of the hER RD is coupled with neither extranuclear localization nor intracellular shuffling.
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Finally, to explore the possible mechanism of how Hsc70 renders unliganded hER inactive in transactivation, associations of the Hsc70 and best characterized HAT coactivator p300 with hER were examined by co-immunoprecipitation (Fig. 6). Reflecting coactivation of the hER mutants by p300, association of p300 with the mutants was detected without Hsc70 interaction. Reversely, Hsc70 was co-immunopreceipitated by the hER mutants harboring the RD, without p300 association. Thus, although Hsc70 itself seems to have no modulatory activity in transcriptional regulation, the association of Hsc70 with hER appears to prevent hER from coactivator recruitment, and Hsc70 is presumed to be dissociated from hER upon liganded binding.
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Discussion |
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Like some other members of the nuclear receptor superfamily, unliganded hER is transcriptionally inactive in vivo and in vitro even when hER is stably bound to its target DNA elements refereed as estrogen response elements (EREs). Steroid hormone receptors, including hER, are distinct from the RXR-heterodimerized non-steroid hormone receptors, like thyroid hormone receptors (TRs), all-trans retinoic acid receptors (RARs) and vitamin D receptor (VDR), in terms of the transcriptional function of unliganded receptors bound to their cognate target gene promoters. These non-steroid hormone receptors are known to suppress the basal transcriptional activity of their target gene promoters in the absence of cognate ligands, and this led to the identification of a number of corepressors and corepressor complexes that often comprise histone deacetylases (HDAC) to convert transcriptionally active chromatin into inactive by histone deacetylation (Kurokawa et al. 1995; Nagy et al. 1997). However, these HDAC-containing complexes have been reported not to associate with unliganded steroid receptors (Kurokawa et al. 1995; Nagy et al. 1997; Yamamoto et al. 2001), reflecting the facts that unliganded steroid receptors are unable to suppress the basal transcriptional activity of target gene promoters. Thus, it is likely that a transcriptionally neutral factor may associate with unliganded steroid receptors through the repression domains to maintain receptors inactive in gene regulations. To address this possibility, we have identified a domain responsible for such inactivation of the receptor function. In hER, a repression domain (RD) was localized in the N-terminal region of the LBD. This repression domain is located close to the helix12 that shifts upon ligand binding to the receptor (Shiau et al. 2002; Wu et al. 2005), and it is therefore possible to suggest that this conformational change or subsequent recruitment of coactivator complexes may induce dissociation of a factor associated with the RD.
Hsc70 as an interactant for the hER RD
Following this hypothesis, we biochemically purified interactants for unliganded hER and found that in comparison with the ligand-bound hER, substantially fewer factors were associated with the unliganded receptor. Using a number of independent methods, we identified Hsc70 as an interactant for the hER RD. Since Hsc70 is a component of a chaperone complex (Ballinger et al. 1999; Alberti et al. 2002), an Hsc70-containing chaperone complex appears to associate with the hER. In Fig. 6, we demonstrated that p300 association with hER is switched with Hsc70 by estrogen binding, and similarly we observed such hormone-induced switching with the p160 member coactivators (data not shown). Thus, this association may reflect an ‘inactive form’ of hER, presumably preventing physical interactions of a number of coactivators/complexes to hER AF-1 and AF-2. Another chaperone complex containing Hsc90 has been known to associate with steroid receptors in cytoplasm (Picard et al. 1990). Similar to Hsc90, Hsc70 also has a predominant cytoplasmic localization, whereas the hER appears to predominantly localize in the nucleus irrespective of presence of ligand. In this study we have provided evidence that Hsc70 associates with unliganded hER in the nucleus.
Recently, CHIP has been identified as a component of a ubiquitin ligase complex that ubiquitinates and thereby promotes degradation of unliganded hER (Tateishi et al. 2004). Interestingly, this CHIP complex is presumed to selectively degrade misfolded hER molecules in the cytoplasm and contains Hsc70 and other Hsc proteins. CHIP is thus likely to control the quality of hER protein, and may associate with the Hsc70 containing chaperone complex together with BAG-1 when required (Alberti et al. 2002). Thus, Hsc70 appears to physically interact with unliganded hER as a unit of the chaperone complex and act as a modulator in regulation of the transactivation function and quality control of hER as well as other not yet identified receptor functions.
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Experimental procedures |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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-associated complexes
HeLa nuclear extracts were loaded onto a P11 phosphocellulose column (Yanagisawa et al. 2002; Kitagawa et al. 2003). After extensive washing with washing buffer (20 mM Tris-HCl pH 7.9, 150 mM KCl, 0.2 mM EDTA, 0.05% NP40, 10% glycerol, 0.5 mM PMSF, 1 mM DTT), bound proteins were eluted by elution buffer (20 mM Tris-HCl pH 7.9, 1 M KCl, 0.2 mM EDTA, 0.05% NP40, 10% glycerol, 0.5 mM PMSF, 1 mM DTT). Immobilized GST-ER LBD fusion proteins were preincubated for 1 h at 4 °C in GST-binding buffer (20 mM Tris-HCl pH 7.9, 180 mM KCl, 0.2 mM EDTA, 0.05% NP40, 0.5 mM PMSF, 1 mM DTT) containing BSA (1 mg/mL) and E2 (10–6M). Bead-immobilized proteins were then incubated at 4 °C for 6–10 h with P11 column-eluted fractions in the presence of 10–6 M E2. After washing with GST wash buffer (GST-binding buffer with 0.1% NP-40) three times, the beads were further washed with a GST wash buffer containing 0.2%N-lauroyl sarkosine (Sarkosyl, Sigma). Complexes associated with E2-bound or unliganded ER were eluted with 15 mM reduced glutathione in elution buffer (50 mM Tris-HCl pH 8.3, 150 mM KCl, 0.5 mM EDTA, 0.5 mM PMSF, 5 mM NaF, 0.08% NP-40, 0.5 mg/mL BSA, and 10% glycerol). For fractionation on glycerol gradient, elutants were layered onto the top of a 4.5 mL linear 100–40% glycerol gradient in GST-binding buffer and centrifuged for 16 h at 4 °C at 40 000 r.p.m. in a SW40 rotor (Beckman). Protein standards used were ovalbumin (44 kDa); ß-globulin (158 kDa); and thyroglobulin (667 kDa) (Watanabe et al. 2001).
GST pull-down assay
GST-fusion proteins were expressed in Esherichia coli, and bound to glutathione-sepharose 4B beads (Pharmacia Biotech) (Yanagisawa et al. 2002). The in vitro translated proteins were then incubated with beads in NET-N buffer (20 mM Tris-HCl pH 7.5, 200 mM NaCl, 1 mM EDTA, 0.5% NP40) with 1 mM PMSF. Bound proteins were separated by 7.5% SDS-PAGE, lightly stained with Coomasie Brilliant Blue to verify equal amounts of fusion protein, and then visualized by autoradiography (Endoh et al. 1999).
Immunoprecipitation
After washing MCF7 cells twice with ice-cold phosphate-buffered saline, the collected cells were resuspended in 1 mL ice-cold lysis buffer (10 mM Tris-HCl pH 7.5, 10 mM NaCl, 3 mM MgCl2, 0.5% NP40), incubated on ice for 30 min, then centrifuged again for 5 min at 500 g. Sedimented nuclear fractions were resuspended in TNE buffer (10 mM Tris-HCl pH 7.5, 0.15 M NaCl, 1 mM EDTA, 1% NP40) and incubated for 30 min on ice. After centrifugation, the supernatants were used as MCF7 whole-cell extracts for immunoprecipitation using anti-hER antibody (anti-ER Ab-1; NEO MARKERS) followed by Western blotting using anti-ER antibody, anti-TRAP220 antibody (Santa Cruz Biotechnology), or anti-Hsc70 antibody raised against the N-terminal region (Santa Cruz Biotechnology) (Yanagisawa et al. 1999).
Transfection and luciferase assay
Cells at 40–50% confluence were transfected with the indicated plasmids using Lipofectamine regent (Gibco BRL) in 12-well Petri dishes (Ito et al. 2004). Total amounts of DNA were adjusted by supplementing with empty vector up to 1.0 µg. Luciferase activity was determined using the Luciferase Assay System (Promega). As a reference plasmid to normalize transfection efficiency, 25 ng of pRL-CMV plasmid (Promega) was co-transfected in all experiments (Takeyama et al. 1999).
Histology
HeLa cells were transfected with hER constructs and GFP-Hsc70 plasmids. The cells were fixed for 20 min in 4% formaldehyde at 25 °C and were incubated with primary antibody B10 that recognize the N-terminal regions of hER. Cy3-conjugated anti-mouse IgG was used as a secondary antibody for immunofluorescence staining. hER and GFP expression were detected using a Zeiss Confocal Laser Scanning System 510.
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Acknowledgements |
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expression vectors and anti-hER antibody (B10) and H. Higuchi for manuscript preparation. This work was supported by a grant-in-aid for priority areas from the Ministry of Education, Science, Sports and Culture of Japan (K.T. and S.K.) and Basic Research Activities for Innovative Biosciences (BRAIN) (S.K.). |
Footnotes |
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* Correspondence: E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp
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Received: 28 July 2005
Accepted: 30 August 2005
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