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Departments of Pharmacology (W.B.D., D.L.V., P.D.R., J.G.S.) and Comparative Medicine (J.G.S.), University of South Alabama College of Medicine, Mobile, Alabama 36688; and Department of Biochemistry and Molecular Biology (D.F.S.), Mayo Clinic Scottsdale, Arizona 85259
Address all correspondence and requests for reprints to: Jonathan G. Scammell, Ph.D., Department of Pharmacology, MSB3130, University of South Alabama, Mobile, Alabama 36688. E-mail: jscammel{at}jaguar1.usouthal.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The binding activity of the GR is dependent on the ordered assembly of a mature receptor heterocomplex (reviewed in Refs. 5, 6). Four proteins (hsp90, hsp70, Hop, and hsp40) are thought to be essential for the conversion of GR to a hormone binding state, which is stabilized by the inclusion of p23 in the complex (7, 8, 9). The omission of any of these proteins might affect the formation of a GR with optimal binding activity. Indeed, altered expression of hsp90 or expression of mutant forms of hsp90 is associated with reduced responsiveness to glucocorticoids (10, 11, 12). We compared the levels of components of the GR heterocomplex in cytosol from SML with those in human lymphocytes (HL). We found that the levels of hsp90, hsp70, Hip, Hop, and p23 were quite similar in these cell types (4). On the other hand, the levels of some of the hsp90-associated immunophilins showed marked differences between squirrel monkey and human cells. Four such proteins have been shown to interact with the hsp90-GR complexes: the FK506-binding immunophilins, FKBP51 and FKBP52, cyclophilin 40 (CyP-40), and the protein phosphatase (PP5) (5). The level of FKBP51 was 13-fold higher in SML than in HL cytosol, whereas FKBP52 in SML was less than one-half that in human cells (4). The idea that an immunophilin might affect GR binding, however, is contrary to the conclusions of several studies regarding the role of these proteins in GR heterocomplexes. First, GR heterocomplexes with hormone-binding activity can be reconstituted in the absence of immunophilins (7, 8). Second, neither FK506 nor cyclosporin A, which inhibit the peptidyl-prolyl isomerase (PPIase) activities of FKBP51 and FKBP52 or CyP-40, respectively, affect GR binding (13, 14).
However, we have preliminary evidence that the inhibitory effect on GR binding of SML cytosol is reproduced with cytosol from COS cells expressing squirrel monkey FKBP51 (4, 15). In this paper, we present data that unequivocally demonstrates that squirrel monkey FKBP51 is a potent inhibitor of GR binding and likely contributes to glucocorticoid resistance in this species. First, we showed that incubation with FK506 and rapamycin increased [3H]dexamethasone binding in cytosol from SML by almost 5-fold. The binding affinity and rank-order of displacement by different steroids were characteristic of high-affinity GR binding. Second, we showed that squirrel monkey FKBP51 is 8-fold more potent than human FKBP51 in affecting GR binding in cytosol mixing studies and nearly 7-fold more potent than human FKBP51 in dexamethasone-induced transcriptional activity in COS cells transfected with human GR. Comparison of the squirrel monkey and human FKBP51 sequences indicates that the two proteins share 94% overall amino acid identity, 92% identity within the PPIase domains, and 99% identity within the tetratricopeptide repeat (TPR) domains. However, we have identified a number of potentially functionally important substitutions present in the N- and C-terminal regions and in sequences joining functional domains of squirrel monkey FKBP51 that may contribute to its species-specific inhibitory activity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell cultures
The squirrel monkey B-lymphoblast cell line (SML) was
transformed with Epstein-Barr virus (17). A HL cell line,
also transformed with Epstein-Barr virus, was provided by Dr. David
Brandon (Oregon Health Sciences University, Portland, OR). COS-7 cells
were obtained from American Type Culture Collection
(Manassas, VA). HL and SML were grown in suspension cultures in RPMI
1640 medium supplemented with 10% FBS, 50 U/ml penicillin G, and 0.05
mg/ml streptomycin. COS-7 cells were grown in monolayers in DMEM
supplemented with 10% FBS and antibiotics. Cells were grown at 37 C in
a humidified atmosphere of 5% CO2-95% air.
GR binding analysis
Cells were washed in PBS and resuspended in HEM buffer [10
mM HEPES (pH 7.4), 2 mM EDTA, 20 mM
sodium molybdate] and lysed by sonication. A soluble fraction
(hereafter referred to as cytosol) was isolated by centrifugation at
100,000 x g for 1 h at 4 C. Protein
concentrations were quantified by the method of Bradford
(18). Fifty-microliter aliquots of cytosol were added to a
mix containing [3H]dexamethasone in the absence
and presence of excess radioinert dexamethasone. In some experiments,
the concentration of radioinert dexamethasone was varied or the effects
of mifepristone, cortisol, progesterone, or 17ß-estradiol
(10-9 to 2 x
10-5
M) on binding were evaluated. After 18 h at
4 C, free steroid was removed by the addition of dextran-coated
charcoal, and the radioactivity in the supernatants was determined.
Specific binding was determined by subtracting nonspecific counts from
total counts. Data were analyzed by nonlinear regression analysis and
visualized by the method of Scatchard (19) using PRISM
software (GraphPad Software, Inc., San Diego, CA).
Expression of FKBP51 in COS-7 cells
The construction of expression plasmids containing either
squirrel monkey or human FKBP51 complementary DNA (cDNA) has been
reported previously (4). The sequences of these inserts
were determined across both strands using the ABI PRISM BigDye
Terminator Cycle Sequencing Ready Reaction Kit and a PE Applied Biosystems 373XL sequencer (Foster City, CA). These
plasmids were used in each of two transfection protocols. First,
24 h before transfection, COS-7 cells were plated in 100-mm dishes
at 8 x 105 cells per dish. Cells were
transfected with 5 µg/dish of either pCI-neo (control) or pCI-neo
containing squirrel monkey or human FKBP51 cDNA (sm51-pCI-neo and
h51-pCI-neo, respectively) using Superfect transfection reagent
(QIAGEN, Valencia, CA). After 3 h, the medium was
replaced, and the cells were incubated for 24 h before cytosol was
collected. The samples were adjusted to the same protein concentration
(2 mg/ml) and mixed for subsequent analysis of GR binding activity.
Second, the effects of expression of squirrel monkey and human FKBP51 on ligand-induced transcriptional activation of GR in COS-7 cells were evaluated. A modification of the method of Bodwell et al. (20) was used. COS-7 cells were maintained as above, except that 39.5 µg/ml L-proline was added to the medium. Cells in log-phase growth were washed in PBS and suspended in electroporation buffer [10 mM piperazine diethanesulfonic acid (pH 7.4), 137 mM NaCl, 2.7 mM KCl, 2.7 mM EGTA, 5.6 mM glucose, 1 mM ATP] at a density of 2.0 x 107 cells/ml, on ice, for 15 min. Aliquots (300 µl) of the cell suspension were mixed with 50 µl TE buffer [10 mM Tris (pH 7.5), 1 mM EDTA] containing 3 µg GR-pcDNA1.1/Amp plasmid, 5 µg MMTV luciferase reporter vector, and 10 µg of either sm51-pCI-neo, h51-pCI-neo, or empty pCI-neo vector and were electroporated using a Gene Pulser II with Capacitance Extender Plus and Pulse Controller Plus modules (Bio-Rad Laboratories, Inc. Hercules, CA) with the PulseTrac system activated and set to deliver a pulse of 174 V. Capacitance (2.0–2.4 millifarads) was adjusted to give a time constant of approximately 140 msec. Electroporated cells were diluted in DMEM with 10% charcoal/dextran-treated FBS, 39.5 µg/ml L-proline, and antibiotics, as above, and plated in 60-mm dishes at a density of 8 x 105 cells/dish. After 18 h, the medium was replaced, and the cells were treated with dexamethasone (0.1–100 nM). Cell extracts were prepared after a further 24-h incubation using 300 µl/dish reporter lysis buffer (PharMingen, San Diego, CA) and were assayed for luciferase activity, as described previously (21). To confirm that the expression of transfected plasmids was similar in each set of cells, the levels of GR and FKBP51 were determined by Western blot analysis, as described previously (4). The endogenous levels of hsp90 were used as an internal standard.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), consistent with
the interaction of FK506 with a large-molecular-weight immunophilin
(22). FK506 had no effect on
[3H]dexamethasone binding in cytosol from HL
(data not shown), consistent with most, but not all, previous studies
showing that FK506 does not affect steroid binding activity of
high-affinity GR complexes (13, 23, 24). We also evaluated
the effects of rapamycin and cyclosporin A. FK506 and rapamycin bind
small and large immunophilins, including FKBP51 and FKBP52, whereas
cyclosporin A binds CyP-40 (22). Rapamycin was as
efficacious as FK506 in stimulating the specific binding of
[3H]dexamethasone in SML cytosol, but
cyclosporin A had no effect (Fig. 2). The
binding activity of FK506-treated SML cytosol was further evaluated to
confirm that the dramatic increase in
[3H]dexamethasone binding observed with FK506
and rapamycin represents bona fide GR binding. First, nonlinear
regression analysis of saturation curves was performed on
[3H]dexamethasone binding in SML cytosol after
incubation with vehicle or 2.3 µM FK506. Specific binding
in control SML cytosol was sufficiently poor that we were unable to
obtain reproducible Kd values. However, in
FK506-treated SML cytosol we obtained an apparent
Kd for [3H]dexamethasone
binding of 6.1 ± 0.4 nM (n = 5), approximating
that determined in cytosol from FK506-treated HL (4.3 ± 0.4
nM, n = 5) used as a high-affinity GR control. Second,
we generated displacement curves with different steroid hormones to
confirm that [3H]dexamethasone binding in
FK506-treated SML cytosol exhibited rank-order competition consistent
with binding to high-affinity GR.
[3H]Dexamethasone binding was displaced by
dexamethasone 
mifepristone > cortisol >
progesterone > estradiol, a rank-order identical to that observed
for [3H]dexamethasone binding in FK506-treated
cytosol from HL (Fig. 3). These results
show that [3H]dexamethasone binding, induced by
FK506 in SML cytosol, represents binding to high-affinity GR; and this
provides support for the role of an FK506-binding protein in mediating
the low binding activity of GR in squirrel monkey cells.
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). Extracts from COS-7 cells expressing
human FKBP51 were much less inhibitory, achieving only a 23%
inhibition of GR binding when the highest concentration of human FKBP51
was included in the assay. Because the levels of expression of squirrel
monkey and human FKBP51 were similar in transfected COS-7 cells
(typical Western blots of cell cytosols are shown in Fig. 5A), we could conclude that squirrel
monkey FKBP51 is approximately 8-fold more potent than human FKBP51 in
inhibiting GR binding.
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). Treatment with dexamethasone induced the
transactivation of GR in COS-7 cells transfected with empty pCi-neo
vector with an EC50 of 0.8 ± 0.2 x
10-9 M (n
= 3) (Fig. 6). Expression of human FKBP51
increased the EC50 by almost 3-fold (2.2 ±
0.2 x 10-9
M, n = 3) and changed the shape of the
dexamethasone-induction curve. The expression of squirrel monkey FKBP51
had a greater effect on the sensitivity to dexamethasone, increasing
the EC50 by 17-fold, compared with control
(EC50 of 13.7 ± 0.2 x
10-9 M, n
= 3) (Fig. 6). The expression of squirrel monkey FKBP51 also affected
the shape of the dexamethasone-induction curve, compared with
control.
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). The mouse FKBP51 was included for
comparison. The squirrel monkey FKBP51 cDNA sequence has been deposited
in GenBank with the accession number AF140759. Squirrel monkey FKBP51
is 94% identical to human FKBP51 and 84% identical to mouse FKBP51.
The TPR domains, made up of three TPR units, and necessary for the
interaction of immunophilins with hsp90 (14, 16, 25, 26),
exhibited striking homology between squirrel monkey and human FKBP51
sequences (Fig. 7, double underline). Squirrel monkey and
human FKBP51 differed in only one amino acid (residue 285) in this
domain. The PPIase domains of squirrel monkey and human FKBP51s
exhibited greater diversity, sharing 92% homology (Fig. 7, single underline) but are identical in conserved
residues required to bind FK506 (22). The consensus
calmodulin-binding motif of squirrel monkey FKBP51 (Fig. 7, dashed underline) differed in one amino acid
(residue 408), compared with the human sequence. Amino acid differences
between squirrel monkey and human FKBP51, which significantly alter
charge and/or polarity, are highlighted (Fig. 7, shaded
residues). Eight amino acid differences in squirrel monkey FKBP51
represent substitutions that impart a more basic charge, which may be
responsible for the more rapid migration of squirrel monkey FKBP51 on
SDS-polyacrylamide gels (Fig. 5). Regardless, detailed site-directed
mutagenesis may be necessary to determine the structural basis for the
increased inhibitory activity of squirrel monkey FKBP51, compared with
the human protein.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The first evidence presented here implicating a role for an FK506-binding protein in glucocorticoid resistance in squirrel monkeys is the dramatic induction of GR binding in squirrel monkey cells by FK506 and rapamycin. Effects of FK506 on GR activity have been reported by several laboratories. Taken together, they showed that FK506 and rapamycin, as well as cyclosporin A, potentiated the induction of a reporter gene by dexamethasone in a cell line derived from L929 cells (34, 35). However, it has subsequently been demonstrated that all three agents cause the accumulation of dexamethasone in L929 cells, suggesting that the potentiation of the hormone response results from a higher intracellular concentration of steroid (36, 37). The studies presented here were performed with cytosol preparations, eliminating a trivial explanation for our finding. The effect of FK506 was reproduced by rapamycin but not cyclosporin A, indicating that this is not a nonspecific action of the immunosuppressants. Furthermore, the effect of FK506 occurred at concentrations consistent with an interaction involving the large-molecular-weight rather than small-molecular-weight immunophilins, such as FKBP12, which occurs with a much lower Kd (22). Rather, we favor the idea that FK506 and rapamycin cause dissociation of FKBP51 from the GR heterocomplex. Because of the relatively low levels of GR in SML and the lack of antibodies for GR immunoprecipitation and analysis of the GR heterocomplex in SML, we do not have direct proof that this occurs. However, FK506 can prevent the association of FKBP51 with GR heterocomplexes. The interaction of squirrel monkey FKBP51 with GR from L929 cells and the inhibitory effect of SML cytosol on GR binding were both inhibited by FK506 when cytosol from L929 cells was mixed with cytosol from SML (4). These results are consistent with studies using FK506 affinity columns, which showed that FKBP51 is not adsorbed from HeLa cell extracts unless it is dissociated from steroid receptor heterocomplexes (38). Thus, the FK506-binding pocket is inaccessible when FKBP51 is associated with the heterocomplex. However, steroid heterocomplexes are in a state of constant disassembly and reassembly; and FKBP51 in SML cytosol, once dissociated from the heterocomplex, cannot reassemble in the presence of FK506. The results of these studies indicate that the presence of squirrel monkey FKBP51 in the GR heterocomplex confers low-affinity binding and that FK506 inhibits this interaction.
On the other hand, most laboratories, including ours, have failed to find any effect of FK506 on GR binding in three cell lines that express high affinity GR (13, 23). In contrast to the low-affinity GR heterocomplex in squirrel monkey cells, high-affinity GR-hsp90 hetercomplexes contain either FKBP52, CyP-40, or the protein phosphatase PP5 (39). Although the presence of PP5 in the heterocomplex has been shown to affect GR activity (40, 41), PP5 has only low-affinity FK506 binding activity (39), and CyP-40 does not bind FK506 (22). FK506 obviously binds FKBP52, but it does so differently than FKBP51. For example, GR heterocomplexes are retained by an FK506 affinity matrix, suggesting that FK506 binds FKBP52, whether in the heterocomplex or not (42). FK506 binding to the GR heterocomplex did not cause activation or dissociation of the complex (42). The results of these studies indicate that FK506 binds to FKBP52 within the mature GR heterocomplex but does not cause functional changes in the receptor. In contrast with this and previous studies, Ning and Sanchez (24) showed that incubation of cytosol from mouse S49 lymphocyte cells with FK506 resulted in a small, but reproducible, increase in the binding affinity of relatively high-affinity GR. However, the molecular basis for this effect was not determined, and the relative levels of FKBP51 and FKBP52 in S49 cells have yet to be determined.
We show here that squirrel monkey FKBP51 is approximately 8-fold more potent than human FKBP51 in two assay systems measuring GR binding and activity. Because the expression of FKBP51 mRNA is increased by glucocorticoids (17, 43), we had hypothesized that the regulation of FKBP51 represents a short-feedback loop by which the sensitivity to glucocorticoids is influenced by previous exposure to hormone (4). We were surprised that squirrel monkey FKBP51 is more potent than the human protein, considering that the two are 94% identical. It is possible that amino acid differences within their functional domains may be responsible for the difference in activity. We have not measured the PPIase activity of squirrel monkey FKBP51, which differs, in seven amino acids in the PPIase domain, from human FKBP51. However, the intrinsic PPIase activity of the immunophilins is not thought to play a role in steroid receptor function (13, 44), suggesting that any difference in PPIase activity of the two proteins likely does not contribute to the differences in the inhibitory activities described here. Rather, the difference in GR inhibitory activity of squirrel monkey and human FKBP51 most likely results from substitutions in other domains. It is unlikely to reside within the TPR domain, which is necessary for the interaction of FKBP51 with hsp90 (16, 45) but is virtually identical between human and squirrel monkey FKBP51. However, sequences in addition to the TPR domain are required for stable association of both FKBP51 and CyP-40 with hsp90 and steroid receptor complexes (45, 26). C-terminal amino acids beyond the TPR domains of the immunophilins are important for preferred association of FKBP51 over FKBP52 in progesterone receptor complexes (45), and it is this region and the N-terminal region that are the most variable between human and squirrel monkey FKBP51.
However, the view that the only important amino acid differences between the two proteins are those that affect the interaction of the TPR domain of FKBP51 with the GR-hsp90 complex may be oversimplistic. Silverstein et al. (46) recently demonstrated that FKBP52 not only interacts with the GR through hsp90 but also binds directly to the GR in the absence of hsp90. They also showed that the interaction with GR did not occur through either the PPIase or TPR domains of FKBP52, although the region of FKBP52 that is involved was not defined. We do not know whether FKBP51 also interacts with the GR directly. However, we noted that the expression of both human and squirrel monkey FKBP51 in COS-7 cells not only shifted, but also changed, the shape of the dexamethasone dose-response curves, suggesting a more complex interaction of this immunophilin with the receptor heterocomplex.
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Footnotes |
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2 Present address: Laboratories for Reproductive Biology, Department
of Pediatrics, University of North Carolina, Chapel Hill, North
Carolina 27599.
Received June 5, 2000.
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-,
Dexamethasone; -
-, mifepristone; -
-, cortisol; -
-,
progesterone; -•-, 17ß-estradiol.
