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Augments Thyroid Hormone Receptor-Mediated Transcriptional Activation1
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Noriyuki Koibuchi, M.D., Ph.D., Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Thorn 1004, Boston, Massachusetts 02115. E-mail: koibuchi{at}rascal.med.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, on thyroid hormone (TH) receptor (TR)-mediated
transcription on a TH-response element (TRE). A transient transfection
study using various TREs [i.e., F2 (chick lysozyme
TRE), DR4 (direct repeat), and palindrome TRE] and TR and ROR1 was
performed. When ROR1 and TR were cotransfected into CV1 cells,
ROR1 enhanced the transactivation by liganded-TR on all TREs tested
without an effect on basal repression by unliganded TR. By
electrophoretic mobility shift assay, on the other hand, although
ROR bound to all TREs tested as a monomer, no (or weak) TR and
ROR1 heterodimer formation was observed on various TREs except when
a putative ROR-response element was present. The transactivation
by ROR1 on a ROR-response element, which does not contain a TRE, was
not enhanced by TR. The effect of ROR1 on the TREs is unique,
because, whereas other nuclear hormone receptors (such as vitamin D
receptor) may competitively bind to TRE to exert dominant negative
function, ROR1 augmented TR action. These results indicate that
ROR1 may modify the effect of liganded TR on TH-responsive genes.
Because TR and ROR are coexpressed in cerebellar Purkinje cells, and
perinatal hypothyroid animals and ROR-disrupted animals show similar
abnormalities of this cell type, cross-talk between these two receptors
may play a critical role in Purkinje cell differentiation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ROR is a novel member of the nuclear hormone receptor (NR)
superfamily and is related to the retinoic acid receptors. At least
three isoforms (ROR1, 2, and 3), which share common DNA- and
putative ligand-binding domains (LBDs) (but possess distinct
aminoterminal domains), are generated by alternative RNA processing in
humans (4). Two isoforms (ROR1 and 4) have been isolated from
mouse brain (5, 6). Although its ligand has not been identified and its
physiological function is not clear, ROR, as manifest by its
messenger RNA (mRNA), is widely expressed, including the central
nervous system (4, 7). ROR1 and 2 bind as monomers to a
hormone-response element (HRE) composed of a 6-bp AT-rich sequence 5'
to a half-site core motif, PuGGTCA (ROR-response element, RORE),
to activate transcription (4).
Because both TR and ROR are transcription factors that share the
common core motif within their response elements, we examined whether
ROR modulates the TR-mediated transcription of TRE. ROR1 binds as
a monomer to a palindromic TRE and to various direct-repeat HREs,
providing an AT-rich sequence precedes one of two core motifs (AGGTCA)
(4). This suggests that a subset of natural TREs containing appropriate
AT-rich sequences could serve as dual-response elements for TR and
ROR. Further, ROR can bind to an HRE containing at least
single-core motif, even without a putative RORE (8). Based on these
results, we hypothesized that ROR may modulate TR action on TREs by
competitively binding to TRE or/and forming heterodimers with TRs. To
test this hypothesis, transfection studies were performed using various
TREs, and TR and ROR1. We believe that this study has physiological
relevance, because both receptors are expressed in the cerebellar
Purkinje cell (5, 6, 9, 10), and perinatal hypothyroid animal and
ROR-disrupted mutant mice (staggerer, sg) show
similar Purkinje cell abnormalities. Dendritic arborization of the
Purkinje cell and synaptic formation between the Purkinje cells and
granule cells are dramatically affected in perinatal hypothyroid rats
(11, 12, 13, 14), whereas Purkinje cells have atrophic dendrites and granule
cell axons that exhibit disturbed synaptic connections in sg
mice (15, 16).
We have previously shown that TH accelerates the expression of ROR
gene in the developing rat cerebellum, suggesting that TH may, in part,
exert its effect by regulating the expression of the ROR gene, which
then regulates the expression of genes essential for normal cerebellar
development (17). However, the modest increase in ROR mRNA content
in TH-treated animals (1.8-fold, compared with that of hypothyroid
animal), only on day 15 of postnatal age, may not explain fully the
involvement of ROR in abnormal neurogenesis seen in the hypothyroid
animal. Therefore, it is necessary to consider another possible
mechanism that involves cross-talk between TR and ROR on TREs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. F2 [chick lysozyme TRE located at
nucleotides -2358 to -2326; half-sites arranged as an inverted
palindrome with nucleotide gap of 6 (18)]; DR4 [half-sites arranged
as direct repeats with nucleotide gap of 4 (19)]; and palindromic TRE,
designed not to contain a putative RORE, were used as typical TREs.
Because the DR4 sequence commonly used in our laboratory contains
AT-rich sequences at the 5' end of the upstream half-site, it may also
serve as a putative RORE (Fig. 1, DR4–1) (19). Hence, another DR4
oligonucleotide lacking such sequence was prepared (Fig. 1, DR4–2).
For an RORE, 3' half-site and spacer sequences of the 
F-crystallin
promoter HRE were used (20). Oligonucleotides containing either the F2
or DR4–1 TRE sequences contain HindIII restriction sites on
both ends, as described previously (19). These were cloned into the
PT109 vector, which contains a viral thymidine kinase promoter coupled
to the luciferase coding sequence (22), or end-labeled with
[32P] -ATP by T4 polynucleotide kinase.
Oligonucleotides containing DR4–2, palindromic TRE, or RORE sequences
with a HindIII site on the 5' end, and a XhoI
site at the 3' end, were prepared and cloned into the PT109 vector or
were end-labeled with [32P] -ATP, as for F2 and
DR4–1. These reporter plasmids were sequenced to ensure that only a
single copy of the TRE had been incorporated.
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1, human TRß1, and mouse RXRß complementary DNAs (cDNAs)
were cloned into the EcoRI site of the expression vector
pcDNA I/Amp (Invitrogen, San Diego, CA). Human ROR1,
cloned in the KpnI-BamHI site of pCMX, was kindly
provided by Dr. V. Giguère, Royal Victoria Hospital, Montreal,
Canada. Both pcDNA I/Amp and pCMX are derived from pCDM8 (23); and
therefore, the promoters required for expression in the mammalian cells
are identical. To eliminate 18 amino acids at the C-terminal end of
ROR1, corresponding to helix 12 of the activation function (AF)2
domain (24), a part of ROR1 cDNA was amplified using a PCR
technique. Sense (5'-GCAGCTTCTACCTGGACATACAG-3', nucleotide 757–779)
and antisense primers corresponding to amino acids 499–505 (nucleotide
1596–1616) with a stop codon, and a BamHI linker at the 5'
end (5'-CGGGATCCTCATGGAGGAAAATGAAGTCGCA-3'), were used. The amplified
fragment and ROR1 cDNA-containing expression vector was then
digested with XbaI (nucleotide 1181) and BamHI,
and ligated.
Cell culture and transient transfection assays
CV1 cells were grown in DMEM containing 10% heat-inactivated
FBS. Approximately 4 h before transfection, culture medium was
changed to DMEM containing 10% heat-inactivated bovine serum, which
was stripped of T3 by treating with activated charcoal for
12 h and constant mixing with 5% (wt/vol) AG1-X8 resin
(Bio-Rad, Richmond, CA) twice for 12 h before filtration
with a 0.22-µm filter. The cells were transfected with expression
(0.1–1.1 µg) and reporter (1.7 µg) plasmids, as well as
RSV-ß-galactosidase control plasmid (1 µg) (25), in 3.5-cm plates,
using the calcium phosphate coprecipitation method (26). Twenty-four
hours after transfection, culture medium was changed, and
T3 was added to a final concentration of 10-6
M unless otherwise indicated, and cells were cultured for
24 h and harvested. Cell extracts were analyzed for both
luciferase (27) and ß-galactosidase (25) activities. Each experiment
was repeated three times in duplicate unless otherwise indicated.
Luciferase activity was normalized to ß-galactosidase activity, and
then calculated as fold-basal luciferase activity with pcDNA I/Amp
vector alone, in the absence of T3. Treatment effect was
examined by ANOVA. A post hoc comparison was made by the
Duncan’s new multiple-range test.
DNA binding/electrophoretic mobility shift assay (EMSA)
TR1, TRß1, RXRß, and ROR1 proteins were translated
in vitro from plasmids, as described above, using the TNT
Coupled Reticulocyte Lysate System with T7 RNA polymerase
(Promega Corp., Madison, WI). These proteins and 20,000
cpm of radiolabeled oligonucleotide probe were then incubated in
binding buffer (19) for 30 min at room temperature. T3 was
also added at a final concentration of 10-6 M
to the samples in some experiments. After incubation, samples were
subjected to electrophoresis on 4% polyacrylamide gels in 0.5x
Tris-borate-EDTA buffer for 75 min at 4 C. The gels were then dried
under vacuum and exposed with x-ray film with an intensifying screen
for 12–48 h.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), were cloned into the PT109 reporter vector,
which contains a viral thymidine kinase minimal promoter and the
firefly luciferase cDNA (21). F2, DR4, and palindromic TREs were used
as typical TREs. The DR4 sequence commonly used in our laboratory
(DR4–1) contains AT-rich sequences at the 5' end of the upstream
half-site, which may serve as a putative RORE (19). Hence, another DR4
oligonucleotide lacking such sequence was prepared (Fig. 1, DR4–2).
For a RORE, 3' half-site and spacer sequences of the F-crystallin
promoter HRE were used (20). These reporter constructs were transfected
(1.7 µg/culture) into CV1 cells with expression vectors containing
TRs and/or ROR1, and RSV-ß-galactosidase (1 µg/culture)
(25).
As shown in Fig. 2, transfection of
either TRß1 or TR1 alone with various TREs resulted in the
repression of basal transcription in the absence of T3, and
activation of transcription in the presence of T3.
Transfection of ROR1 alone (0.1 µg/culture) did not induce any
change in transcription, even on DR4–1, which contains a putative
RORE-like sequence. When TR and ROR1 were cotransfected, ROR1
significantly enhanced the liganded TR-induced transactivation without
changing the repression of transcription mediated by unliganded TR. The
extent of potentiation differed somewhat among TREs, and between TR1
and TRß1. An increase of approximately 2-fold was seen on DR4–1 and
F2, and a 35% increase on a palindromic TRE and DR4–2 with TRß1.
The effect was always smaller with TR1 and ranged from 50% (F2) to
20% (palindromic TRE; not statistically significant). We also tested
the effect of TRs on ROR1-induced transcriptional activation on a
RORE. ROR1 induced an 80% increase in transcription. However,
cotransfection of TRs with ROR1 did not further increase the
transcription after T3 treatment (Fig. 3).
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1, relative to
TR, changed the magnitude of enhancement. When ROR1 alone was
transfected, a dose-dependent increase in transactivation was observed
only on DR4–1 (Fig. 4), in
which AT-rich sequences were located upstream of 5' of the half-site
(Fig. 1). However, the maximal increase was only 50%, with a large
amount of ROR1 (1.0 µg). Cotransfection of TR and ROR1, in the
DNA ratio of 1:1, significantly increased the magnitude of the
transcription (Fig. 4). Further increases in the amount of
cotransfected ROR1, relative to TR, however, did not potentiate the
effect further. Instead, when a 10-fold excess of ROR1 containing
plasmid was added, the potentiation was greatly reduced.
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1 is dependent on
T3 concentration. T3 was added to the culture
medium at different final concentrations
(10-8–10-5 M) at 24 h after
transfection, and cells were harvested at 24 h after
T3 treatment. At 10-8 M
T3, ROR1 did not augment the TRß1-induced
transactivation but did potentiate the TR1-induced transactivation
on F2, DR4–1, and DR4–2 (Fig. 5). A significant effect of ROR1 on
TRß1-induced transactivation was seen, with greater amounts of
T3 on these TREs. On the other hand, although ROR1
significantly potentiated the effect of TR1 with a low amount of
T3 (10-8 M), the further increase
in this effect was not seen at higher T3 doses (Fig. 5). On
the palindromic TRE, ROR1 did not alter either TRß1 or
TR1-induced transactivation with 10-8 M
T3. A significant effect of ROR1 on TRß1- or
TR1-induced transactivation was seen with T3 at
10-7 M; but again, further potentiation was
not seen on the palindromic TRE at higher T3 doses.
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1 directly activates transcription on TREs, we
produced a mutant ROR1 (RORmut), in which 18 amino acids
at the C-terminal end, corresponding to helix 12 of the AF2 domain
(28), was truncated. As expected, no transactivation was observed when
RORmut alone was transfected with various TRE-containing
reporter vectors. Cotransfection of TRß1 and RORmut,
however, significantly enhanced liganded TRß1-induced transactivation
without changing basal repression by unliganded TRß1, although the
magnitude of potentiation was less than that with wild-type ROR1
(Fig. 6). A similar tendency was
observed with TR1 and RORmut on palindrome and F2 TREs.
RORmut did not potentiate the effect of unliganded and
liganded TR1 on DR4–1 and DR4–2. On a RORE, RORmut did
not induce any transactivation but repressed ROR1-induced
transactivation in a dose-dependent manner (Fig. 7). A 5-fold excess of
RORmut completely blocked wild-type ROR1-induced
transactivation.
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1 could be
caused by direct protein-protein interaction between the two receptors.
To examine the potential interaction of TR and ROR1, a DNA
binding/EMSA was performed. In vitro translated TR, ROR1,
and RXRß were mixed with 32P-labeled oligonucleotides
containing a single copy of a TRE. When TRß1 alone was mixed with the
oligonucleotide, it bound preferentially to F2, DR4–1, and DR4–2 as
an homodimer in the absence of T3 and was dissociated by
T3 treatment. TR1 also preferentially bound to F2 as an
homodimer and to DR4–1 and DR4–2 as monomer (Fig. 8). Homodimeric TRß1 and monomeric
TR1 were also seen on the palindromic TRE, but these complexes were
weak. When TR1 or TRß1 was mixed with RXRß, two heterodimer
bands were observed, reflecting dimers formed with the two major
in vitro translated products of RXRß (21). When ROR1
was mixed with oligonucleotides containing TREs, a distinct complex was
always observed (Fig. 8). Because the size of this band was identical
to that seen on an oligonucleotide containing a RORE (data not shown),
this band was considered to be monomer complex. When TR and ROR1,
ROR1 and RXRß, or all three proteins were mixed together, no
additional bands were observed on F2 and palindromic TREs. However, the
intensity of the ROR1 band became weaker. This is particularly
evident when TR1 and ROR1 were mixed together.
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1/ROR1 heterodimer was seen on
DR4–1, which contains an AT-rich sequence located at 5' of the
half-site (Fig. 1). Such a heterodimer was not seen when the nucleotide
spacing between the two half-sites was changed from 4 to 5 or 3
nucleotides (DR5 and DR3, respectively), indicating that this
heterodimer preferentially binds to TRE (data not shown). When TRß1
and ROR1 were mixed with DR4–1, a broader band, which might contain
an additional band with slightly slower mobility than ROR1 monomeric
band, appeared. Electrophoresis, for a longer time (2.5 h), however,
did not allow detection of an additional band. A much weaker
TR1/ROR1 heterodimer was also seen on DR4–2, which does not
contain any AT-rich sequence at the 5' region of the half-sites. These
results indicate that the AT-rich sequence in the 5' region enhances
TR1/ROR1 heterodimer binding to the TRE, even it does not
serve as a functional RORE, as shown by transfection assay. No
TRß1/ROR1 heterodimer was seen on DR4–2. On the RORE, no TR
monomer or homodimer, and heterodimer of TR/RXRß, TR/ROR1, or
ROR1/RXRß was detected; only ROR1 monomer binding was observed
(data not shown). Neither the addition of CV1 cell nuclear extract,
which may contain putative adaptor proteins and/or endogenous ligand to
promote TR and ROR1 interaction, nor changes in the binding
conditions of the EMSA produced an additional heterodimer (data not
shown). Addition of serum, which may contain endogenous ligand, also
did not promote further interaction.
We also examined the interaction of ROR1 with TR, as well as with
other NRs, by the glutathione S-transferase (GST)-pull down assay.
In vitro translated 35S-labeled ROR1
interacted GST-TR-LBD. However, this interaction may be nonspecific,
because ROR1 interacted with all other GST-NRs tested, such as
retinoic acid receptor ß (GST-RARß), GST-RXRß LBD, and
GST-estrogen receptor LBD (data not shown). Binding of ROR1 and RAR
is, in particular, not likely, because ROR1/RAR heterodimer was not
seen on a RARE by EMSA (18). Further, the transcriptional activation by
RAR on RARE was not augmented by ROR1 (18).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 augments liganded TR-induced
transcriptional activation on all TREs examined, such as F2,
palindromic TRE, and DR4, without altering basal repression by
unliganded TR. On the contrary, liganded TR did not alter
ROR1-induced transcriptional activation on a RORE. These results
suggest the involvement of ROR1 in regulation of gene expression by
TR in cells in which TR and ROR1 are coexpressed.
The effect of ROR1 on TR action, seen in the present study, is in
contrast to the general effect of NRs to inhibit transcription on TREs
by a dominant negative mechanism. Several NRs and their isoforms, such
as c-erbA2, v-erbA, mutant TR, and vitamin D receptor (VDR), are
capable of binding TREs as monomer, homodimer, and heterodimer with
RXR, without induction of transcriptional activation (24, 29, 30, 31). In
particular, VDR has its distinct target HRE but is also capable of
binding TREs without effecting transcription (24). ROR1 also has a
distinct target HRE (RORE) and is capable of binding to various TREs
without transcriptional activation when it is transfected alone. In
contrast to VDR, however, ROR1 augments the TR function. This
indicates that ROR may function as a transcriptional coregulator by
forming a protein complex with TR, as has been documented for RXR. A
decrease in transcriptional potentiation by a mutant ROR1, in which
its AF2 domain is mutated, supports this possibility, because the AF2
domain is involved in transcriptional activation of HREs by interacting
with coactivators (28, 32, 33). When the AF2 domain of RXR is mutated,
a similar decrease in transactivation by TR is seen. However, for
reasons that remain unclear, a TR-ROR1 interaction was not readily
detected by EMSA. The heterodimer formation that we observed does not
correlate well with transfection data. For example, ROR1 showed a
strong potentiation on TRß1 action on F2 by transfection without an
apparent heterodimer on EMSA. The absence of apparent heterodimer
formation on EMSA could be caused by weak interactions between the two
proteins, or absence of a putative adaptor protein or endogenous ROR
ligand that may be required to promote the interaction of TR and
ROR1. Of note, this apparent discrepancy between the transfection
and EMSA results apparently is not peculiar to this TR-ROR1
interaction. Indeed, similar augmentation was seen between SF-1 (a
member of the NR superfamily) and Egr-1 (a member of the zinc finger
transcription factor family) on LHß gene promoter, using transient
transfection assay, without an apparent protein interaction by EMSA
(34).
The ability of the AF2-mutated ROR1 to retain the effect on liganded
TR function indicates that a non-AF2-dependent mechanism may, at least
in part, mediate the effect. Harding et al. (8) have shown
that ROR1 is bound to nuclear corepressors, such as N-CoR and SMRT
in vitro, in the absence of DNA. This interaction is not
dependent on the AF2 region, although the binding was about half of
that normally seen between corepressors and Rev-Erba or TR (8). On the
RORE, on the other hand, only the AF2-truncated form of ROR1 binds
to N-CoR. Our group has found that N-CoR can interact with TR in the
presence of T3 in vivo (Takeshita and Chin,
unpublished observation). Another corepressor, SMRT, is also shown to
interact, in part, with liganded TR (35). These interactions are,
however, much weaker than those with unliganded TR, possibly because
T3 may alter the equilibrium between inactive and active
states of TR (33). Because ROR1 can bind to these corepressors with
or without an intact AF2 region, in the absence of DNA, ROR1 may
exert its effect, in part, on TR-induced transcription by titrating
these corepressors from liganded TR.
As described above, we have hypothesized the involvement of ROR in
TH action in development of the cerebellum. This is based on the
abnormal neurogenesis in sg mice similar to that seen in
hypothyroid animals. The mutant mice exhibit normal TR expression and
TH levels, but they show diminished expression of pcp-2 and
thymidine kinase activity, which are regulated by TH (36, 37). Although
we have previously shown that TH accelerates ROR expression
transiently during development (17), the modest increase in ROR mRNA
content in TH-treated animals (1.8-fold, compared with that of
hypothyroid animals) only on day 15 of postnatal age may not fully
explain the involvement of ROR in abnormal neurogenesis seen in the
hypothyroid animal. Taken together with the present study, we have
shown that ROR is not only regulated by TH but also potentiates the
liganded-TR action on TREs. This result suggests that ROR may be
required for full function of TR in the developing cerebellum. This
scenario is feasible in the Purkinje cell, because both ROR and TR
genes are expressed in this cell type (5, 6, 9, 10). The expression of
ROR gene in the postnatal cerebellum is increased with age (17, 37).
The pattern of increase is essentially similar to that of TRß (10).
Therefore, the similarity of abnormal morphogenesis of Purkinje cells
in sg mice and hypothyroid animals may be caused by a
decrease in TR action caused by the lack of ROR expression to
activate the transcription of the genes containing TREs, as well
as direct actions of ROR on the genes containing ROREs. In the
present study, however, we used CV1 fibroblast, rather than cerebellar
cells, because a clonal cell line derived from Purkinje cells is not
available. Because cell-specific activation and repression of
transcription by ROR has been reported (8), CV1 cells may not be the
ideal cell type to use in studying the effect of ROR in TR action.
However, we have confirmed, by Northern blot, that small amounts of ROR
mRNA are present in CV1 cells. Thus, as a consolation, endogenous ROR
is not likely to be a confounding feature in these cells. We have also
obtained preliminary data using P19 cells, a embryonic carcinoma cell
line that can be differentiated to neuronal cells (19). We did not see
any enhancement of TRß effect by ROR1, but the TRß-induced
transactivation by itself was much greater than that in CV1 cells.
Because fairly large amounts of ROR are expressed in this cell type
(6), the endogenous levels of ROR may be sufficient to induce
potentiation of TR action.
The effect of ROR to augment other NR-induced transcription on their
HRE may not be specific only for TR-TRE system. Although ROR did not
augment RAR/RXR-induced transcription on RARE, even though
it contains an RORE (20), a current report has shown the potentiation
of peroxisome proliferator-activated receptor
(PPAR)-mediated transcription, on a PPAR-response element
without forming a PPAR/ROR heterodimer (39). Because ROR is
widely expressed in many organs, as well as the cerebellar Purkinje
cell (7), ROR may not only induce transactivation on RORE but also
play an important role in transcriptional regulation by many NRs, by
modulating their effect on their HREs.
In summary, ROR1 augments the TR-induced transactivation on several
TREs, without altering basal repression by unliganded TR in CV1 cells.
The maximal effect of TR was observed with a 1:1 ratio of transfected
TR and ROR1; further increases in ROR1 did not result in
additional potentiation. The effect was T3 dose-dependent
when TRß and ROR1 were cotransfected but not with TR1 and
ROR1. By EMSA, no (or weak) heterodimer of TR and ROR1 was
observed on the TRE except when a putative RORE was present. Because TR
and ROR are coexpressed in the cerebellar Purkinje cells, and
perinatal hypothyroid animal and ROR-disrupted mice show similar
Purkinje cell abnormalities, it is possible that the effect of ROR1
on the transcription activity of TR on various TREs may play a critical
role in differentiation of this cell type.
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Acknowledgments |
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1 cDNA. |
Footnotes |
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2 Present address: Molecular and Cellular Endocrinology Branch,
NIDDK/NIH, Bethesda, Maryland 20892.
Received August 20, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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nuclear receptors. Genes Dev 8:538–553 in staggerer mice. Nature 379:736–739[CrossRef][Medline]
, an orphan
nuclear receptor required for cerebellar development. Mol Endocrinol 11:1737–17462 in selected tissues:
cerebellar Purkinje cells as a model for ß1 receptor-mediated
developmental effects of thyroid hormone in brain. Proc Natl Acad Sci
USA 88:3887–3891- and ß-thyroid hormone receptor mRNAs,
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potentiates transactivation by the peroxisome proliferator-activated
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D. Roy, N. L. Angelini, H. Fujieda, G. M. Brown, and D. D. Belsham Cyclical Regulation of GnRH Gene Expression in GT1-7 GnRH-Secreting Neurons by Melatonin Endocrinology, November 1, 2001; 142(11): 4711 - 4720. [Abstract] [Full Text] [PDF]
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 P. M. Yen Physiological and Molecular Basis of Thyroid Hormone Action Physiol Rev, July 1, 2001; 81(3): 1097 - 1142. [Abstract] [Full Text] [PDF]
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