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Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Silvia Misiti, G. W. Thorn Research Building, Room 1005, Brigham and Women’s Hospital, 20 Shattuck Street, Boston, Massachusetts 02115. E-mail: misiti{at}rascal.med.harvard.edu
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recent discoveries that NR-associated coactivators and corepressors appear to be directly involved in chromatin remodeling have complicated this picture. The corepressors, SMRT and N-CoR, form complexes with histone deacetylases, suggesting that chromatin remodeling by histone deacetylation is a possible mechanism for receptor-mediated repression. Further, most of the coactivators have been found to possess intrinsic histone acetyltransferase activities (6, 7, 8, 9), in addition to several putative activation domains.
At the tissue/organ messenger RNA (mRNA) level, the coactivators and corepressors identified to date are ubiquitously expressed (2, 3, 10, 11), and most, if not all, cells contain both types of coregulators. However, the relative expression of coactivator and corepressor mRNAs has not been determined. In this study we examined the expression of known coactivator [steroid receptor coactivator-1 (SRC-1) (10) and E1A-associated 300-kDa protein (p300) (11)] and corepressor [SMRT) (3) and (N-CoR) (2)] genes in a large number of tissues, including several endocrine glands and cell lines, to provide a comparative analysis of their mRNA expression patterns.
The mRNAs encoding several members of the steroid/thyroid hormone receptor superfamily [TRs, retinoic acid receptors (RARs), and retinoid X receptors (RXRs)] have been shown either to increase or decrease in response to treatment with their cognate hormones (12, 13, 14) or with heterologous hormones [i.e. effect of estradiol (E2) on different TR and RXR isoforms (Schomburg, L., manuscript in preparation)]. In addition, the regulation of estrogen receptor mRNA by E2 differs in direction depending on the tissue (15), and there is a tissue-specific regulation of glucocorticoid receptor mRNA levels in states of glucocorticoid excess and depletion (16).
Thus, we next addressed whether coactivator and corepressor mRNA levels are hormonally modulated. We examined the effects of thyroid hormone (T3) treatment on the levels of mRNAs encoding SRC-1, SMRT, and N-CoR, which are factors that directly interact with TR, and of p300, which binds with SRC-1 (17, 18), in GH3 cells and in the anterior pituitary (AP), where all TR isoforms are present (19).
Inasmuch as there are examples of multihormonal regulation of genes in the pituitary (20, 21, 22), and TR and estrogen receptor (ER) both belong to the NR superfamily, we also studied the effects of E2 on the expression of SRC-1, p300, SMRT, and N-CoR mRNAs. Additionally, because the AP is influenced by sex steroids (23), we compared the levels of mRNAs for these cofactors in the pituitary glands of male and female rats.
In this report we show that there is a marked variation in the tissue-specific expression and differential hormonal regulation of the mRNAs encoding SRC-1, p300, SMRT, and N-CoR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]deoxy-CTP was purchased from New England
Nuclear Corp. (Boston, MA), and the random primed DNA labeling kit was
obtained from Stratagene (La Jolla, CA).
In vitro studies
GH3 cells were grown in DMEM supplemented with 10%
FCS at 37 C in a 5% CO2 atmosphere. When the cells reached
50–75% confluence, the medium was exchanged for DMEM containing 10%
charcoal- and AG1-X8 (Bio-Rad, Richmond, CA)-stripped FCS. After
48 h, the stripped medium was exchanged; vehicle, E2
(10 nM), or T3 (100 nM) was then
added, and the dishes were incubated for the times indicated in
Results.
In vivo studies
Adult male and female Sprague-Dawley rats (250 g; Charles River,
Wilmington, MA) were used. The animals, maintained according to the
guidelines of the Harvard Medical Area Standing Committee on Animals,
had access to water and standard laboratory chow ad libitum.
The animals were housed at an ambient temperature of 22 C with
alternating 12-h light, 12-h dark cycles. Euthyroid animals received sc
injections of E2 (0.5 µg/100 g BW), T3 (30
µg/100 g BW), or vehicle (sesame oil and 15% dimethylsulfoxide in
0.9% saline) and were killed after the time periods indicated.
Immediately after decapitation, the tissues of interest were removed
and frozen in liquid nitrogen.
Northern blot analysis
The frozen tissues (a pool of six APs or pineal glands, or 100
mg pooled hypothalamic fragments/preparation) or pellets containing
approximately 5 x 107 GH3 (rat pituitary
tumor), AtT20 (mouse pituitary tumor), Rat-1 (rat embryo), NIH-3T3
(mouse fibroblast), 293 (human embryonic kidney cells transformed by
the early region of adenovirus), COS-7 (simian virus 40-transformed
African green monkey kidney), CHOK1 (Chinese hamster ovary), CV1
(African green monkey kidney), and HeLa (human cervix epitheloid
carcinoma) cells were homogenized in 5 ml SDS-Tris-based buffer [0.1
M Tris-HCl (pH 8.0), 0.5 M LiCl, 10
mM EDTA, 1% SDS, and 5 mM dithiothreitol]
with the aid of a Teflon-glass homogenizer. Polyadenylated
[poly(A)+]-enriched RNA was isolated directly from the
homogenates using magnetic oligo-(deoxythymidine)25
polystyrene beads (Deutsche Dynal, Hamburg, Germany) according to the
manufacturer’s instructions. Total RNA was prepared from cultured
cells by the acid guanidinium thiocynate-phenol-chloroform procedure
using RNAzol B (Biotex Laboratories, Houston, TX). Total and
poly(A)+ RNA (10 µg/lane) was separated by
electrophoresis in denaturing agarose gels (2.2 M
formaldehyde and 1.5% agarose), transferred to nylon membranes by
diffusion (Nytran NY 12 N, Schleicher and Schuell, Dassel, Germany),
and cross-linked by UV irradiation. Hybridizations were performed under
high stringency conditions (42 C, 16 h; in 50% formamide, 0.5%
SDS, 100 µg salmon DNA, 0.9 M NaCl, 12 mM
EDTA, and 0.09 M sodium phosphate, pH 7.4) with 50 ng
complementary DNA (cDNA) fragments randomly labeled with
[32P]deoxy-CTP to high specific activities
(>109 cpm/µg). The following cDNA fragments were used as
probes: a 0.8-kb HindIII fragment of human cDNA encoding
SRC-1 (24), a 2.5-kb SacI fragment of human cDNA
encoding TRAM-1 (25), a 0.8-kb XbaI-SmaI fragment
of human cDNA encoding p300 (11), a 0.8-kb BamHI fragment of
mouse cDNA encoding N-CoR (2), a 1.4-kb BamHI fragment of
human cDNA encoding SMRT (3), and as a standard, a 0.7-kb fragment of
rat cDNA encoding cyclophilin (26). The membranes were washed at a
final stringency of 0.2 x SSPE-0.3% SDS (0.2 x SSPE =
30 mM NaCl, 2 mM sodium phosphate, and 0.2
mM EDTA, pH 7.4) at 60 C (mouse and human cDNA probes) and
65 C (rat cDNA probes), respectively. The membranes were analyzed by a
PhosphorImager (Molecular Dynamics, Sunnyvale, CA; >24-h exposure) and
then subjected to autoradiography (X-Omat, Eastman Kodak, Rochester,
NY). All data were corrected for variability in loading by
normalization to the amount of cyclophilin mRNA. Thereafter, blots were
stripped by washing in 0.02 x SSPE-0.3% SDS at 90 C for 15 min.
The complete removal of hybridizing cDNA probes was confirmed by
autoradiography. The same membrane was used for the subsequent
hybridizations with the other probes.
Statistical analysis
ANOVA was used to assess the statistical significance, and
post-hoc comparison was made using Duncan’s new multiple
range test.
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Results |
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SRC-1 is expressed as a major RNA transcript of 7.5 kb in many tissues,
including thyroid, pineal gland, adrenal, and hypothalamus. SRC-1 mRNA
was present in all of the rat tissues examined, although the amounts
varied among the organs tested, with relatively high levels detected in
brain and pituitary. Next, we analyzed the expression of p300, SMRT,
and N-CoR mRNAs, each migrating as an approximate 9-kb species. These
mRNAs were detected in anterior pituitary, on which more extensive
studies of hormonal regulation were performed, and in every rat tissue
analyzed. The expression pattern for each cofactor mRNA was different
(Fig. 1
). Thus, SRC-1, p300, SMRT, and
N-CoR genes are ubiquitously expressed, but also display
tissue-specific expression.
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shows a marked variation in the levels of coactivator and corepressor
mRNA among the cell lines examined. For SRC-1, the major transcript
(
7.5 kb) was highly expressed in GH3 cells (Fig. 2);
this finding prompted us to choose this system for further hormonal
regulation studies (Figs. 3 and 5). In
keeping with the ubiquitous expression of the p300 and N-CoR proteins
in cell lines (2, 27), we detected their 9-kb mRNAs in all cell lines
examined, with p300 mRNA being highly expressed in 293 cells and CV-1
(Fig. 2). The major N-CoR mRNA is about 9 kb; a minor species (5.0
kb) was present in all cell lines. As the same band was not present in
the tissue distribution blot (Fig. 1
), it is unclear if represents a
nonspecific signal or a minor transcript (Fig. 2). The highest level of
SMRT mRNA (9 kb) was detected in CV1 and COS-7 cells (Fig. 2), and
no signal was present in GH3 cells. For all probes,
additional, shorter transcripts could also be detected at lower
abundance in different cell lines. SRC-1 belongs to a novel 160-kDa NR
coactivator gene family that includes TIF2 (28) and TRAM-1 (25). To
compare the expression of different members of this family, TRAM-1
recently cloned in our laboratory was included in these experiments
(Fig. 2). The expression pattern of TRAM-1 mRNA (9 kb) was different
from that of SRC-1 in the same cell lines. The highest level of TRAM-1
mRNA was detected in COS-7 cells, and no signal was present in
GH3 cells.
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), with a return to basal values
after 48 h. In contrast, T3 treatment did not alter the p300 and N-CoR mRNA levels present in GH3 cells (data not shown). We also attempted to study SMRT mRNA levels in this system. However, the hybridization signals were not sufficient to be analyzed quantitatively. As a positive control, T3 treatment of GH3 cells resulted in an approximately 4-fold increase in GH mRNA in the same RNA samples, similar to previous reports (29).
Regulation by T3: in vivo
To study the effects of thyroid hormone on coactivator and
corepressor mRNAs in vivo, euthyroid male rats received
single (ip) injections of T3 and were killed 0, 2, 4, 6, 8,
24, 48, and 96 h after treatment. Pharmacological doses of
T3 (30 µg/100 g BW) were injected to examine the rapid,
hence probably direct, effects of thyroid hormone (30). Pituitary SRC-1
mRNA levels showed a slow and slight, but statistically significant,
induction, reaching 1-fold above control values 24 h (Fig. 4). The same blots were stripped and
rehybridized with the other probes. No significant
T3-dependent changes were observed for p300, SMRT, and
N-CoR mRNA levels in the anterior pituitary (data not shown).
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Regulation by E2: in vitro
GH3 cells were propagated in growth medium containing
FCS, as described above, and then maintained in a defined medium
containing stripped serum for 48 h before treatment. The cells
were incubated in the presence or absence of E2 (10
nM) for 6 and 24 h. Total RNA was isolated and then
subjected to RNA blot hybridization using specific
32P-labeled cDNA fragments. Treatment of GH3
cells with E2 decreased SRC-1 mRNA levels; within 6 h
after E2, a decrease to 34% of the control levels was
observed, which reached a minimum value (28% of the control) after
24 h (Fig. 5).
In contrast, E2 (10 nM) did not significantly
alter the levels of the single, approximately 9-kb p300 and N-CoR mRNA
species present in GH3 cells (Fig. 2). SMRT mRNA levels
were not analyzed in this system because of the low expression in this
cell line.
Regulation by E2: in vivo
We next evaluated the effect of estrogen (E2) on the
expression of coactivator and corepressor mRNAs in vivo.
Estrogen (single ip injection; 0.5 µg/100 g BW) regulated the
expression of pituitary SRC-1 and SMRT mRNA levels in male rats. Two
hours after injection, a significant decrease in SRC-1 mRNA levels was
evident (Fig. 6A). The maximum
suppressive effect was obtained 4–6 h after injection, reaching 56%
of control values. SRC-1 mRNA returned to basal levels 48 h after
hormone treatment. The effects of E2 on SMRT mRNA levels
were more rapid and greater than those on SRC-1. Two hours after the
injection of E2, SMRT mRNA levels increased to 1.8-fold the
control levels, returned to basal values only 4 h after injection,
and showed a significant decrease to 65% of control values 6 h
after E2 injection (Fig. 6B). However, these SMRT mRNA
levels did not return to basal levels even 48 h after
injection.
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The same blots used to show down-regulation of SRC-1 and up-regulation
of SMRT by E2 were stripped and rehybridized with p300- and
N-CoR-specific probes. Again, E2 did not change p300 and
N-CoR mRNA levels (Fig. 6, C and D), as expected from the in
vitro studies.
Gender-related difference
A tissue-specific gender difference was observed in the expression
of SRC-1 steady state mRNA levels in anterior pituitary. Preparations
from female APs contained 40% less SRC-1 mRNA than those from male
rats (Table 1). This result may be
correlated with the down-regulation of SRC-1 mRNA levels by
E2 treatment that we observed in GH3 cells and
in AP by Northern blot analysis. These gender differences were specific
for SRC-1 mRNA levels and were not observed in hypothalamic and pineal
gland preparations. In addition, the levels of p300, N-CoR, and SMRT
mRNAs did not display gender differences in AP (Table 1), hypothalamus,
or pineal gland (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our studies show that the tissue-expression patterns of these genes vary among the tissues and cell lines examined, suggesting that although the coactivator and corepressor genes are ubiquitously expressed, their relative expression is tissue dependent. Additionally, the presence of smaller mRNA transcripts that seem to be tissue specific raises the possibility of tissue-specific alternatively spliced mRNA isoforms encoding these coregulators. Hayashi et al. suggested that a splicing variant of SRC-1, named SRC-1E, is expressed more abundantly than SRC-1, and this variant enhances T3/TR-mediated trans-activation more efficiently than other isoforms (31). Although generally the abundance of coactivator and corepressor mRNAs reflects the abundance at the protein level, further studies are required to determine the protein content for each coregulator and its variants.
The marked variation observed in coactivator and corepressor mRNA expression prompted us to study the possible hormonal modulation of their genes. Regulation of the NR expression is a common mechanism for modulating cell responses to hormones, neurotransmitters, and growth factors, and it is well known that the NR gene expression is hormonally regulated (32). Individual factors in a given multiprotein complex may serve as communicators that integrate distinct physiological signals. This concept has been suggested by the recent findings that the activity of the TR coactivator, Trip 230, is negatively regulated by Rb, a protein for cell cycle progression and cellular differentiation (33), and that the retinoids up-regulate corepressor SMRT, but not coactivator Trip1, mRNA levels in neuroblastoma cell lines (34).
We have investigated the effects of T3 and E2 on SRC-1, p300, SMRT, and N-CoR gene expression in rat pituitary cells (GH3) in vitro and in AP in vivo. The AP is a good system for our studies because it expresses a wide variety of peptide and steroid hormone receptors, and it is the only gland in which all TR isoforms are present (35, 36).
Our results show that T3 up-regulates SRC-1 mRNA levels in GH3 cells and in the AP. However, the magnitude of the effect in vivo was lower and slower compared with the in vitro effect. The difference may be explained by the presence of a mixed population of five different endocrine cell types in the AP gland and by the fact that the somatotrope, from which GH3 is derived, accounts for only 50% of the adenohypophyseal cells (37). Further immunocytochemistry studies are in progress to assess the cellular distribution of SRC-1 expression in the AP. In addition, Hodin et al. have shown that T3-mediated changes in ligand binding in the pituitary may provide only a partial reflection of the changes in TR expression occurring within the pituitary because of the differential effect of T3 on TR isoform mRNA expression in the pituitary (32). We did not observe any major T3 effects on p300, SMRT, and N-CoR mRNA levels when the same experimental conditions were used. Nonetheless, SRC-1 mRNA levels were stimulated by T3, although the magnitude of the change in vivo was slight.
We have shown that estrogen has opposing effects on SRC-1 and SMRT gene expression. In fact, we found a consistent decrease in SRC-1 mRNA levels within 4–6 h after treating rats with E2 and a rapid increase in SMRT mRNA levels within 2 h of treatment, followed by an equally rapid decrease. E2 also did not affect the p300 and N-CoR gene expression in our in vitro and in vivo experiments. Although the physiological relevance of these coactivators and corepressors remains poorly understood, we suggest that tissue sensitivity to hormones may be modified by the relative abundance of SRC-1, p300, SMRT, and N-CoR. In tissue in which the coactivators and corepressors may be limiting, even small variations in their mRNA levels could influence the balance of these proteins, and thus the hormonal response. For example, the responses to ligands of the estrogen receptor is tissue dependent (38).
In agreement with our finding that the SRC-1 mRNA levels are down-regulated by estrogen, we observed a significant gender difference in SRC-1 gene expression in the pituitary, with higher mRNA levels found in preparations from male rats than in those from female rats. The biological significance of this gender difference in SRC-1 mRNA levels is also unclear. We believe that it might be related to a sex-specific difference in the distribution of subpopulations of pituitary cells. Additional in situ hybridization and immunohistochemistry studies must be performed to determine the cellular distribution and the relative levels of coactivator and corepressor mRNAs and proteins in the different populations of AP cells.
In conclusion, we show tissue to tissue variation in the expression of SRC-1, p300, SMRT, and N-CoR genes. These findings are consistent with our hypothesis that the relative expression of coactivator and corepressor genes may contribute to the heterogeneity of hormonal responses observed in normal and malignant tissues. We also show that the hormonal status differentially affects the expression of the coactivator and corepressor genes. These hormonal effects may not only modulate target gene regulation, but also may have physiological consequences for normal programs of growth and development and for cellular function.
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Acknowledgments |
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Received October 13, 1997.
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