COMMUNICATION
The Repressed Nuclear Receptor CAR Responds to Phenobarbital in
Activating the Human CYP2B6 Gene*
Tatsuya
Sueyoshi,
Takeshi
Kawamoto,
Igor
Zelko,
Paavo
Honkakoski
, and
Masahiko
Negishi§
From the Pharmacogenetics Section, Laboratory of Reproductive and
Developmental Toxicology, NIEHS, National Institutes of Health,
Research Triangle Park, North Carolina 27709 and the
Department of Pharmaceutics, University of
Kuopio, FIN-70211 Kuopio, Finland
 |
ABSTRACT |
The endogenous CYP2B6 gene becomes
phenobarbital (PB) inducible in androstenol-treated HepG2 cells either
transiently or stably transfected with a nuclear receptor CAR
expression vector. The PB induction mediated by CAR is regulated by a
conserved 51-base pair element called PB-responsive enhancer module
(PBREM) that has now been located between
1733 and
1683 bp in the
gene's 5'-flanking region. An in vitro translated CAR
acting as a retinoid X receptor
heterodimer binds directly to the
two nuclear receptor sites NR1 and NR2 within PBREM. In a stably
transfected HepG2 cell line, both PBREM and NR1 are activated by PB and
PB-type compounds such as chlorinated pesticides, polychlorinated
biphenyls and chlorpromazine. In addition to PBREM, CAR also
transactivates the steroid/rifampicin-response element of the human
CYP3A4 gene in HepG2 cells. Thus, activation of the
repressed nuclear receptor CAR appears to be a versatile mediator that
regulates PB induction of the CYP2B and other genes.
 |
INTRODUCTION |
Metabolism by the liver microsomal
CYPs1 plays an important role
in the detoxification of xenochemicals such as pharmaceutical drugs and
environmental contaminants. Ironically it can often result in
activation of xenochemicals to more toxic and/or carcinogenic products
(1). Inducible gene transcription by exposure to xenochemicals is
characteristic for CYPs, which increases the organism's defense capability against toxicity and carcinogenicity. Since the discovery of
PB induction 35 years ago (2), PB has served as a prototype for a large
group of structurally and functionally diverse xenochemicals that
induce CYP2B genes. A PB-responsive enhancer activity was first associated with a 177-bp DNA sequence (
2318/
2155 bp) of the
rat CYP2B2 gene in primary hepatocytes (3) and was later confirmed using an in situ injection method (4).
Furthermore, the corresponding sequence was also found in the mouse
Cyp2b10 gene (5). The enhancer activity of the 177-bp
sequence has now been delimited to a 51-bp element PBREM in
Cyp2b10 (6) and similar DNA element in CYP2B2 (7,
8). The nuclear orphan receptor heterodimer CAR-RXR has been identified
as a transactivator of PBREM (9).
The nuclear orphan receptor CAR was originally characterized as a
constitutive activator of an empirical set of retinoic acid response
elements (RAREs) (10). Consistently, CAR-mediated PBREM activity
observed in HepG2 cells was PB-independent (9). Thus, CAR remains to be
established as a true signal mediating PB induction. Most recently, the
CAR-mediated transactivation of RAREs has been reported to be repressed
by 3
-androstenol and androstanol (11). Considering the functional
properties of CAR, we have examined whether CAR can activate the
endogenous CYP2B gene and whether activation is
PB-dependent in a stable HepG2 cell line transfected with a
CAR expression vector. We have also located the PBREM sequence in the
human CYP2B6 gene and demonstrated PB responsiveness of PBREM in HepG2 cells.
 |
EXPERIMENTAL PROCEDURES |
Chemicals--
TCPOBOP was synthesized using the method of Kende
et al. (12). 3
-Androstenol was obtained from Steraloids
(Wilton, NH); o,p'-DDT, methoxychlor, and PCB
were from AccuStandard (New Haven, CT). All other chemicals were
purchased from Sigma.
Plasmids--
CAR-
cDNA was amplified as described in a
previous report (9) and cloned into between the BamHI and
XhoI site of pCR3 vector. In the case of the luciferase
reporter plasmid, the 160-bp thymidine kinase (tk) promoter was
amplified from pBLCAT2 plasmid and cloned into the BglII and
HindIII sites of pGL3-Basic vector containing the firefly
luciferase reporter gene (Promega). The complementary oligonucleotides
of human and mouse PBREM and the triplicate human NR1
((5'-gatcACTGTACTTTCCTGACCTTGgatc-3')3) sequences were
synthesized and were cloned in front of the tk promoter
(BglII site), resulting in PBREM-tk-luciferase and
(NR1)3-tk-luciferase reporter gene plasmids. The
(ER6)3-tk-CAT reporter gene plasmid was constructed by
insertion of (5'-GATCAATATGAACTCAAAGGAGGTCAGTG-3')3 into
the pBLCAT-2 basic vector (13).
Cells and Transfection Assay--
HepG2 cells were cultured in
minimal essential medium supplemented with 10% fetal bovine serum and
antibiotics (9). A stable transfected HepG2 cell line (g2car-3) was
transfected with a pCR3-mCAR expression vector and selected by neomycin
resistance. The enhancer-containing plasmids (0.1 µg) were
co-transfected with pRL-SV40 (0.2 µg) into g2car-3 cells (17-mm well)
using calcium phosphate co-precipitation and incubated for 24 h.
Luciferase activity was measured simultaneously using the
Dual-Luciferase Reporter Assay System (Promega). Promoter activities
were determined from three independent transfections and calculated
from firefly luciferase activities normalized against Renilla
luciferase activities of an internal control pRL-SV40 plasmid. For the
CAT assays, a CYP3A4 (ER6)3-tk-CAT reporter gene plasmid (1.0 µg) was co-transfected with pCMV
gal (Promega) as an
internal control. 3
-Androstenol (4 µM) was included in
the culture medium, which produced maximal repression of the
CYP2B6 gene in the CAR-transfected HepG2 cells
(EC50
1 µM).
RT-PCR--
To measure CYP2B6 mRNA, total RNA was
subsequently prepared from HepG2 and g2car-3 cells using TRIZOL reagent
(Life Technologies, Inc.). One-twentieth of each cDNA synthesized
from 2 µg of RNA was subjected to 37- and 29-cycle amplifications of
CYP2B6 mRNA from HepG2 and g2car-3 cells, respectively.
The primers (5'-CACCCTAACACCCATGACCG-3' and
5'-GATCACACCATATCCCCGGA-3') were designed from the reported sequences
(GenBankTM accession number J02864) across intron
1 of the CYP2B6 gene. PCR reactions were performed
using Taq DNA polymerase (Promega) with TaqStart antibody
(CLONTECH) at 94 °C for 30 s, 55 °C for 30 s, and 72 °C for 40 s. The amplified DNA (276 bp) was
separated on a 1.5% agarose gel and visualized with staining by
ethidium bromide.
-Actin mRNA was amplified as an internal control.
Gel-shift Assays--
hCAR and RXR
were translated using
TNT-coupled reticulocyte lysate system (Promega). The double-stranded
oligonucleotides of the human NR1, NR2 (5'-
gatcCATGGACTTTCCTGAACCAAgatc-3'), or ER6 were labeled using
[32P]dCTP and DNA polymerase Klenow fragment. Gel-shift
assays were performed as described previously (9). For competition,
200-fold excess of each cold probe was included in the incubation.
DNA Sequencing--
The cosmid clone F17390 containing the
humanCYP2B6 gene was generously provided by Dr. H. W. Mohrenweiser (14). A 5 kbp of the 5'-flanking region was amplified by
PCR using primers generated from exon 1 and the cosmid vector, digested
to smaller fragments (0.5-1.0 kbp) by sonication, blunt-ended with T4
DNA polymerase, and cloned into the SmaI site the pUC18
vector. Over 100 pUC18 clones were sequenced, and sequence data were
assembled by Sequencher to complete the 1.8-kbp 5'-flanking region of
CYP2B6 gene. The GenBankTM accession number of
this sequence is AF081569.
 |
RESULTS AND DISCUSSION |
The levels of CYP2B6 mRNA were measured in the
transfected HepG2 cells to obtain more direct evidence that CAR can
mediate PB induction of the CYP2B gene (Fig.
1A). First, HepG2 cells are transiently transfected with CAR-expressing plasmids and then treated
with 3
-androstenol alone or both 3
-androstenol and TCPOBOP (the
most potent PB-type inducer known). RT-PCR assay reveals that
endogenous CYP2B6 mRNA is present in CAR-transient
transfected HepG2 cells but not in nontransfected HepG2 cells.
Androstenol treatment represses CYP2B6 mRNA in
CAR-transfected HepG2 cells. Subsequently, TCPOBOP dramatically induces
CYP2B6 mRNA in 3
-androstenol-treated CAR-transfected
HepG2 cells. These transient transfections showed that the endogenous
CYP2B6 gene can be regulated by CAR and PB.

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Fig. 1.
CAR-mediated induction of CYP2B6
mRNA in HepG2 cells. A, HepG2 cells were
transfected with pCR3-mCAR (1.0 µg/21-mm well) 24 h prior to
treatment with TCPOBOP (250 nM) in the presence or absence
of 3 -androstenol (4 µM). For all experiments, total
RNAs were prepared from duplicated cultures treated separately and were
subjected to RT-PCR and agarose gel electrophoresis. DNA bands were
visualized by ethidium bromide. B,
dose-dependent induction by PB or TCPOBOP. Various
concentrations (indicated on the top of each line) of PB or
TCPOBOP were added at 70% confluent g2car-3 cells in 12-well dish with
1-ml culture medium containing 4 µM 3 -androstenol,
followed by further 24-h incubation before performance of RT-PCR.
|
|
We then constructed a stable HepG2 cell line (named g2car-3)
transfected with a CAR-expressing plasmid in order to measure mRNA
more consistently. First, stable expression of CAR resulted in a
dramatic increase of CYP2B6 mRNA in the g2car-3 cells as indicated by intense bands after just 29 cycles (Fig. 1B).
However, 37 cycles of PCR does not amplify mRNA from HepG2
(left two lanes in Fig. 1A). The expression
levels of CYP2B6 mRNA in g2car-3 cells are roughly
comparable with that of Cyp2b10 mRNA in PB-treated mouse
livers. Using this stable cell line, dose-dependent
induction was examined with PB and TCPOBOP. As expected,
CYP2B6 mRNA is induced in a dose-dependent
manner by the inducers in 3
-androstenol-treated g2car-3 cells (Fig.
1B). The results show unequivocally that CAR mediates
induction of the endogenous CYP2B6 gene in response to PB
and TCPOBOP.
The mouse PBREM is a 51-bp DNA enhancer consisting of two nuclear
receptor DR4 motifs (NR1 and NR2) flanking a NF1 binding site (6). The
corresponding 51-bp DNA is found in a
1.7-kbp region of the human
CYP2B6 gene, while its 5' to 3' orientation is opposite from
the mouse and rat PBREM sequences (Fig.
2). The 16-bp NR1 site of human PBREM
differs by only 1 base from mouse NR1, making NR1 the most conserved
sequence between human, mouse, and rat PBREM elements. The NR1 site,
thus, may be the key element conferring enhancer activity to PBREM.
Since the human NR2 is 87% sequence identical to NR1 and also binds to
in vitro translated CAR-RXR heterodimer (Fig.
3A), the function of NR2 may
be redundant. On the other hand, the least conserved NF1 site may not
be critical for PB responsiveness in agreement with our previous
findings (9). Consistent with our previous findings (9), neither PB or
3
-androstenol (10 µM) affected binding of in
vitro translated CAR (data not shown). Moore et al.
have also shown that androstenol and androstanol do not inhibit binding
of CAR to RARE sequences, while they appear to dissociate SRC-1 from
CAR (11). Therefore, it remains to be investigated whether PB can
recruit transcriptional co-activators to activate PBREM.

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Fig. 2.
Localization and sequence of the human
PBREM. The antisense sequence of the human PBREM is shown in
comparison with mouse PBREM and the corresponding sequences of
PB-inducible rat CYP2B1 and CYP2B2 genes
(GenBankTM accession numbers U30327 and S51970,
respectively). The 5'-flanking sequence of the human CYP2B6
gene is tentatively numbered using the putative transcription start
site of the mouse Cyp2b10 gene. NR1 and NR2 represent two
DR4 nuclear receptor motifs, which are boxed, and their
direct repeats are indicated by arrows, while NF1 denotes a
putative nuclear factor 1 binding site. Indirect repeats (ER6) in
CYP3A4 gene are indicated by arrows with
solid lines and a possible DR4 motif within ER6 is indicated
by arrows with broken lines.
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Fig. 3.
PB responsiveness of CAR-mediated
transactivation in g2car-3 cells. A, binding of
in vitro translated CAR and RXR to NR1 and NR2. Gel shift
was performed with either 32P-labeled NR1 or NR2 probes.
For competition, 200-fold cold probe was included in gel-shift assay.
B, the promoter activities were calculated from three
independent transfections and are shown by firefly luciferase
activities normalized against Renilla luciferase activities for the
internal control pRL-SV40 plasmid. The arrows indicate the
5' to 3' orientations of the PBREM sequences. Andro.,
3 -androstenol. Luci, luciferase.
|
|
We then examined whether CAR-mediated transactivation of PBREM is
PB-inducible. For this, the PBREM-tk-luciferase reporter gene was
transfected into 3
-androstenol-treated g2car-3 cells, which were
then induced by TCPOBOP. CAR-mediated transactivation was enhanced by
5-10-fold in g2car-3 cells (Fig. 3B). NR1 alone appears to
be sufficient to confer PB responsiveness to CAR-mediated transactivation. Moreover, the (NR1)3-tk-luciferase
reporter gene displays a high TCPOBOP responsiveness (Fig.
3B), suggesting that PB and TCPOBOP probably induce
CAR-mediated transactivation by displacing 3
-androstenol. These
transactivations by CAR are totally consistent with the induction of
the endogenous CYP2B6 gene (Fig. 1). Thus, the nuclear
receptor CAR can mediate PB-inducible transcription of the
CYP2B6 gene through its binding to the NR1 site of PBREM. 3
-Androstenol is one of the 16-androstenes in human urine and is
also present in circulation (15). The reported peripheral plasma
concentration (nanomolar) of 3
-androstenol in men is substantially lower than the micromolar concentration required to repress
CAR-mediated transactivation in HepG2 cells. Although 16-androstenes
may accumulate to higher levels and/or steroids may repress CAR at
substantially lower concentration in liver, how CAR is actually
repressed in liver remains as a question of major interest.
PBREM is a versatile enhancer that responds to a great number of
PB-type inducers with very diverse structures (6). Therefore, known
PB-type inducers o,p'-DDT, methoxychlor, PCB, and
chlorpromazine were selected to examine whether induction by these
inducers is also CAR-mediated. All four xenochemicals are found to
induce CYP2B6 mRNA in 3
-androstenol-treated g2car-3
cells (Fig. 4A). The
(NR1)3-tk-luciferase reporter activity is also increased by these PB-type inducers (Fig. 4B). In contrast,
3-methylcholanthrene (3-MC), dexamethasone (DEX), and clofibrate, which
are classical CYP1A, CYP3A, and CYP4A inducers, respectively, neither
transactivate PBREM nor induce CYP2B6 mRNA (Fig. 4, A
and B). A slight increase by 3-MC of mRNA may not be
mediated by CAR, since 3-MC did not activate PBREM. DEX actually
represses both mRNA and PBREM activity. It is known that DEX
treatment decreases CYP2B mRNA in rat hepatoma-derived Fao cells
(16), while DEX induces the Cyp2b gene in mouse primary hepatocytes (17). The mechanism by which DEX represses PBREM remains to
be investigated. CAR, nevertheless, displays a versatility to mediate
transactivation by a number of known PB-type inducers and a specificity
which corresponds only to that of PB-type inducers.

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Fig. 4.
Versatility of CAR to respond to various
PB-type inducers. A, duplicates of g2car-3 cells (21-mm
well) were treated by chlorpromazine (CPZ) (25 µM), o,p'-DDT (50 µM),
methoxychlor (50 µM), or PCB (50 µM) for
24 h. For controls, cells were also treated with DEX (50 µM), 3-MC (1 µM), or clofibrate (200 µM) for 24 h. Total cellular RNA was subjected to
RT-PCR. These concentration of inducers were selected from our previous
paper (6). The amplified DNAs were separated on an agarose gel and
stained by ethidium bromide. B, for transactivation, the
(NR1)3-tk-luciferase gene reporter plasmid (0.1 µg) was
co-transfected with pRL-SV40 plasmid into g2car-3 cells. The cells were
incubated with various chemicals for 24 h, harvested, and
subjected to luciferase assay.
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PB is a pleiotropic agent that induces various drug-metabolizing
enzymes, including the CYP3A gene (18, 19). As shown in Fig.
5, A and B,
in vitro translated CAR-RXR heterodimer binds to the
steroid/rifampicin-responsive ER6 element of human CYP3A4 gene and mediates PB-inducible transactivation of the response element
in the g2car-3 cells. Therefore, the pleiotropic PB actions can, in
part, be explained by the ability of CAR-RXR heterodimer to bind to
distinct nuclear receptor motifs. Alternatively, since ER6 is reported
to be activated by PXR and PB (13), PB may activate multiple nuclear
orphan receptors to induce various CYP genes. These effects
of PB are concerted to increase hepatic metabolic capability. For
example, proliferation of endoplasmic reticulum increases membranes
into which CYP protein is inserted, while heme synthesis and glucose
metabolism supply the prosthetic group protoheme and the reducing agent
NADPH, respectively. Does CAR play a role in endoplasmic reticulum
proliferation and/or regulate glucose metabolism? Whether CAR is
responsible for these pleiotropic actions of PB remains a focus of
future investigation.

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Fig. 5.
Induction of the human
CYP3A4 gene in g2car-3 cells. A, gel-shift
assay of the binding of in vitro translated mCAR and RXR
to 32P-labeled ER6 as probe. For competition, 3A4 denotes
cold ER6 oligonucleotide. In NR1m
(5'-gatcATTATACTTTTCTTGAACTTGgatc-3'),
3 bases (underlined) were mutated from the original NR1
sequence. B, (ER6)3-tk-CAT reporter gene plasmid
(1.0 µg) was transfected into g2car-3 cells (60-mm dish), which were
treated with TCPOBOP (250 nM) for 24 h in the culture
medium. Cells were then harvested for and CAT activity determined.
pSV gal (Promega) was co-transfected as an internal control.
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|
Nuclear orphan receptors have now emerged as major mediators of
xenochemical-inducible transcription of CYP genes. In
addition to CAR, pregnenolone X receptor, and peroxisome
proliferator-activated receptor
activate xenochemical-induced
transcription of the CYP3A and CYP4A genes,
respectively (20-23). As a family of proteins with a low affinity to
diverse ligands and with a binding flexibility to various DNA motifs,
the nuclear receptors may collectively induce a large set of CYP and
conjugation enzymes in response to myriads of xenochemicals. Induction,
in turn, could result in increased metabolism of xenochemicals and
endogenous substrates (e.g. steroids and lipids) to produce
other potential ligands of nuclear receptors. For example, the
pesticide methoxychlor is metabolized by CYP2B enzyme to estrogenic
products (24). As methoxychlor also activates CAR and CYP2B expression,
CAR could be directly involved in increasing availability of ligands
for estrogen receptors. A functional cross-talk between CYP and nuclear receptor superfamilies may have important consequences in the physiological and pathological responses to xenochemicals.
 |
FOOTNOTES |
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§
To whom all correspondence should be addressed: Pharmacogenetics
Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709. Tel.: 919-541-2404; Fax: 919-541-0696; E-mail:
negishi{at}niehs.nih.gov.
 |
ABBREVIATIONS |
The abbreviations used are:
CYP, cytochrome P450;
CAT, chloramphenicol acetyltransferase;
PB, phenobarbital;
PBREM, PB-responsive enhancer module;
tk, thymidine
kinase;
RARE, retinoic acid response element;
RT-PCR, reverse
transcriptase-polymerase chain reaction;
TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene;
NR, nuclear receptor;
3
-androstenol, 16-(5
)-androsten-3
-ol;
o, p'-DDT,
1,1,1-trichloro-1,2-bis(o,p'-chlorophenyl)ethane;
PCB, 2,3,3',4',5',6-hexachlorobiphenyl;
bp, base pair(s);
kbp, kilobase pair(s);
3-MC, 3-methylcholanthrene;
DEX, dexamethasone;
RXR, retinoid
X receptor;
PBREM, phenobarbitalresponsive enhancer module;
CAR, constitutively activated receptor.
 |
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