Endocrinology Vol. 140, No. 2 618-623
Copyright © 1999 by The Endocrine Society
Hormonal Induction of Mouse Selenocysteine Transfer Ribonucleic Acid (tRNA) Gene Transcription-Activating Factor and Its Functional Importance in the Selenocysteine tRNA Gene Transcription in Mouse Mammary Gland
Kazushige Adachi,
Teruo Tanaka1,
Hiroshi Saito2 and
Takami Oka
Laboratory of Molecular and Cellular Biology, National Institutes
of Diabetes, Digestive, and Kidney Disease, National Institutes of
Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: LMCB/NIDDK/NIH, Building 8, Room 309, Bethesda, Maryland 20892.
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Abstract
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Mouse selenocysteine transfer RNA (tRNA) gene transcription-activating
factor (mStaf) is a transcriptional activator that enhances RNA
polymerase III-dependent mouse selenocysteine tRNA
(tRNASec) gene transcription. The DNA-binding activity of
mStaf in mouse mammary gland undergoes developmental changes, reaching
a maximal level during the period of lactation. In this study, we
employed an organ culture system to examine the hormonal regulation of
mStaf binding and its role in the tRNASec transcription in
the mammary gland. The results showed that mStaf binding in mammary
explants was stimulated by treatment with the lactogenic hormones, PRL,
insulin, and hydrocortisone and that a specific MEK inhibitor, PD98059,
inhibited the hormonal stimulation of mStaf binding. Other kinase
inhibitors, such as a Janus kinase inhibitor and a calmodulin kinase
inhibitor, had no apparent effect. Northern and Western blot analyses
revealed that the level of both mStaf messenger RNA and protein was
enhanced by the lactogenic hormones and was reduced by the concomitant
treatment with PD98059. The mitogen-activated protein kinase activity
in cultured explants was rapidly induced and maintained at high levels
by the lactogenic hormones. We also found that the lactogenic hormones
increased the amount of tRNASec in a time-dependent manner,
which followed the increase in mStaf binding in cultured mammary
explants. These results support the view that mStaf plays a key role in
the hormonal stimulation of tRNASec transcription in the
mammary gland.
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Introduction
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UNDER THE influence of hormones, the
mammary gland undergoes marked developmental changes to express its
differentiated function during lactation. These changes can be induced
in vitro by cultivating mammary tissue explants in the
presence of the appropriate hormones. The synergistic actions of
insulin, hydrocortisone, and PRL stimulate the functional
differentiation of mammary epithelium by inducing the expression of
milk protein genes (1). This system provides an opportunity to
elucidate the molecular mechanisms by which hormones regulate gene
expression in mammalian cell differentiation. Studies show that the
lactogenic hormones stimulate transcription of the casein gene, which
encodes the major milk protein, by inducing specific transcription
factors, including signal transducer and activator of transcription-5
(STAT5), through the Janus kinase (JAK)/STAT signaling pathway (2, 3).
The functional differentiation of the mammary gland is accompanied by
the increased expression of genes encoding various housekeeping
proteins that support the enhanced metabolic and functional activities
of mammary epithelium during lactation. For example, the activities of
two selenoenzymes, T4 5'-deiodinase and glutathione
peroxidase, in the mammary gland have been shown to increase during
lactation (4, 5). 5'-Deiodinase plays an essential role in the
production of a more active thyroid hormone, T3, which
serves to enhance lactational activity (4), whereas glutathione
peroxidase catalyzes the oxidation of glutathione and the reduction of
H2O2 for a cellular antioxidant defense
mechanism (5). These enzymes contain selenocysteine, which is required
for their enzymatic activities. At the present time, however, the
regulatory mechanisms involved in the production of these selenoenzymes
in the mammary gland have not been elucidated.
The biosynthesis of selenoproteins requires selenocysteine transfer (t)
RNA (tRNASec) as a donor of selenocysteine (6, 7).
Transcription of the tRNASec gene is mediated by RNA
polymerase III (Pol III) and is dependent on its upstream promoter,
consisting of distal and proximal sequence elements and a TATA motif
(8, 9, 10, 11, 12). The distal sequence element contains an important activator
element (AE) that mediates transcriptional activation of the gene (13).
Recently, we cloned from mouse mammary gland a complementary DNA (cDNA)
encoding an AE-binding protein that stimulates transcription of the
mouse tRNASec gene and named this protein mouse
selenocysteine tRNA gene transcription-activating factor (mStaf) (14).
The binding activity of mStaf in mouse mammary gland has been shown to
undergo marked developmental changes as a function of reproductive
stage, reaching a maximal level during lactation (14). It also has been
shown that the level of tRNASec parallels the changes in
mStaf binding, reaching a highly elevated level in lactating mammary
glands. These results suggest that mStaf plays a key role in the
regulation of tRNASec gene expression during lactogenesis.
In addition, it is conceivable that the mStaf-binding activity is
hormonally, regulated because the development of the mammary gland is
stimulated by the synergistic actions of polypeptide and steroid
hormones.
To investigate the regulation of mStaf binding and its role in
tRNASec gene expression in the mammary gland, we examined
the effect of lactogenic hormones on mStaf binding and the amount of
tRNASec transcript using mammary culture systems. Our data
indicate that the lactogenic hormones increase the level of mStaf
binding and its synthesis through the mitogen-activated protein kinase
(MAPK) pathway and enhance the tRNASec transcript in mouse
mammary gland.
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Materials and Methods
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Materials
Bovine PRL was obtained from the Hormone Distribution Program
(NIDDK, NIH). Hydrocortisone and porcine zinc insulin were purchased
from Calbiochem (La Jolla, CA). The antiserum directed
against the carboxyl-terminal domain of mStaf (amino acid residues
613–626) was generated in rabbits. Protein kinase inhibitors, PD98059,
tyrphostin B42, and W-7, were purchased from
Calbiochem.
Animals
Age-matched virgin (3-month-old) C3H/HeN female mice were
obtained from the Animal Center of the NIH. Animal care and study
protocol were in full compliance with the NIH guidelines.
Organ culture
Mammary explants from virgin mice were cultured in DMEM
supplemented with the indicated hormones as described previously (1).
The concentrations of hormones used were as follows: insulin, 5
µg/ml; hydrocortisone, 1 µg/ml; and PRL, 5 µg/ml.
Preparation of nuclear extracts and electrophoretic mobility shift
assays (EMSAs)
Nuclear extracts were prepared from mouse mammary glands
according to the method described previously (15) and used for EMSA and
Western blot analyses.
Nuclear extracts were mixed with 3 µg poly(dI-dC) (Sigma Chemical Co., St. Louis, MO) in the reaction buffer containing
14 mM HEPES (pH 7.9), 12% glycerol, 90 mM
NaCl, 2.5 mM MgCl2, and 1 mM
dithiothreitol (DTT) and incubated for 15 min on ice. EMSA were
performed as previously described (14), using a 32P-labeled
double-stranded oligonucleotide corresponding to the -233/-198 region
of the mouse tRNASec gene (MW;
5'-GGCGCTGCTTCCCAGAATGCAAGGCGCTATGCAAAT-3'). Competition experiments
were performed using unlabeled MW or mutated type mouse
tRNASec gene (MM;
5'-GGCGCTGCTTCAACGAAGTAAAGTATCTATGCAAAT-3').
Another labeled, double-stranded oligonucleotide, (SW;
5'-TCACGTTCTTGGAATTGAAGGGAC-3') was used for detection of STAT5 (16).
Antibody supershift experiments were performed by preincubating nuclear
extracts with 1 µl antiserum against mStaf or preimmunized serum at
25 C for 1 h.
Northern blot analysis
Total RNA from cultured mammary explants was prepared by the
acid-phenol extraction method (Life Technologies,
Gaithersburg, MD). Polyadenylated RNA was prepared for detection of
mStaf messenger RNA (mRNA) using the
mini-oligo(deoxythymidine)-cellulose spin column kit (5Prime-3Prime,
Inc., Boulder, CO). It was separated on a formaldehyde-agarose gel
electrophoresis, blotted, and hybridized with a 32P-labeled
probe bearing the +667/+1292 region of mStaf cDNA. The blot was then
exposed for 24–36 h at -80 C. For detection of tRNASec,
total RNA was separated by electrophoresis on a 6% polyacrylamide-8
M urea gel (Novex, San Diego, CA), transferred
to a Nylon+ membrane (Novex) by
electroblotting, and hybridized with a 32P 5'-end-labeled
oligonucleotide (5'-GCACCCCAGACCACTGAGGATCATCCGGGC-3') specific for the
mouse tRNASec. The amounts of tRNASec were
estimated by densitometric tracing of autoradiographic films.
Western blot analysis
Nuclear extracts (50 µg protein) were electrophoresed on a 8%
SDS-polyacrylamide gel and then transferred to a polyvinylidene
difluoride membrane (Novex). After treatment with blocking
reagents (Tris-buffered saline, pH 7.6, containing 5% skim milk),
membranes were incubated with antiserum against mStaf (1:1000 dilution)
or preimmunized serum in Tris-buffered saline, pH 7.6, containing 0.5%
skim milk for 1 h at room temperature. The presence of antibody
binding to mStaf was detected by the enhanced chemiluminescence system
(Amersham, Arlington Heights, IL).
MAPK assay
Mammary explants were homogenized in 10 mM phosphate
buffer containing 1 mM EDTA, 1 mM DTT, 400
mM KCl, 10% glycerol, 5 µg/ml aprotinin, 5 µg/ml
leupeptin, 1 mM phenylmethylsulfonylfluoride, 5
µM NaF, 2 mM Na2VO4,
and 50 µM sodium glycerophosphate. The homogenates were
centrifuged for 3 min to remove cellular debris at 10,000 x
g at 4 C, and supernatants were recovered. The supernatant
(400 µg protein) was incubated with rabbit polyclonal antibody
against Erk2 (Santa Cruz Biotechnology, Inc., Santa Cruz,
CA) for 1 h at 4 C, and then the reaction mixture was treated with
protein A-Sepharose beads at 4 C for 4 h. The immunoprecipitated
products were recovered by centrifugation and washed three times with
the phosphate buffer and twice in a kinase assay buffer [25
mM HEPES (pH 7.4), 10 mM MgCl2, 10
mM MnCl2, and 1 mM DTT]. The
washed immunoprecipitates were resuspended in the kinase buffer.
Appropriate amounts of washed materials were incubated in the presence
of 10 µg myelin basic protein and 50 µM
[
-32P]ATP (6000 Ci/mmol) at 25 C for 5 min. The
reaction was terminated by the addition of Laemmli SDS buffer. The
reaction mixtures were subjected to SDS-PAGE (14%), and
autoradiography was performed.
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Results
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Lactogenic hormones induce mStaf binding in mouse mammary gland in
culture
As shown in Fig. 1A
, the effects of
various combinations of lactogenic hormones on mStaf binding to the AE
region in cultured explants were examined by EMSA using a
32P-labeled double stranded oligonucleotide corresponding
to the -233/-198 region of the mouse tRNASec gene. The
binding was virtually undetectable in uncultured explants (lane 1) or
explants cultured in the absence of hormones (data not shown), whereas
the distinct presence of a slower migrating band was detected in the
triple hormone-treated explants (lane 5). However, the combination of
insulin and PRL produced a less intense band at the same position (lane
4). Other combinations of lactogenic hormones were virtually
ineffective. In addition, no mStaf binding was detected in explants
cultured in the presence of hydrocortisone and PRL (data not shown).
The triple hormone-induced band was judged to be specific for mStaf by
competition experiments using wild-type (MW) and mutated (MM)
competitors (Fig. 1B, lanes 3 and 4). Furthermore, the addition of the
antibody specific to mStaf in the binding reaction resulted in the
formation of a supershifted band (lane 5 and cf. lane 2),
whereas the supershifted band was not produced by the addition of
preimmunized serum (data not shown).
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Figure 1. Induction of mStaf binding by lactogenic hormones
in cultured mouse mammary gland explants. A, Effects of various
combinations of hormones on mStaf binding. Mammary gland explants from
virgin mice were cultured in medium containing the indicated
combination of insulin (I), hydrocortisone (H), and PRL (P) for 24
h. mStaf binding was determined using 5 µg nuclear extracts from
uncultured explants (lane 1; U) and cultured explants with the
indicated hormones (lanes 2–6) as described in Materials and
Methods. B, mStaf binding was determined using 5 µg nuclear
extracts from uncultured explants (lane 1; U) and cultured explants
with insulin, hydrocortisone, and PRL for 24 h (lanes 2–5; IHP).
Competition experiments were performed using a 100-fold molar excess of
either unlabeled wild-type (MW; lane 3) or mutated (MM; lane 4)
oligonucleotide as competitors. Antibody supershift experiments were
performed using the nuclear extracts from the IHP-treated explants and
1 µl antiserum specific for mStaf (lane 5). The arrow
indicates the mStaf band. C, The time course of IHP-induced mStaf
binding. Mammary gland explants from virgin mice were cultured in the
medium containing IHP or insulin (I) for the indicated times. The data
in A–C represent one of three independent experiments, which gave very
similar results.
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Figure 1C
depicts the change in mStaf binding in mammary explants
cultured in the presence of a combination of insulin, hydrocortisone,
and PRL (IHP) or insulin. mStaf binding in the triple hormone-treated
explants was detectable after 12 h and increased until 48 h
(lanes 3–5). The level of mStaf binding remained elevated at 72 h
(data not shown). No increase in mStaf binding occurred in explants
cultured with insulin alone (lane 2). These results indicate that PRL
in combination with insulin and hydrocortisone is critical for the
enhancement of mStaf binding in mouse mammary tissue.
The MAPK signaling pathway is involved in the hormonal stimulation
of mStaf binding and its production
Recent studies indicated that PRL transmits its signal by
activating the JAK2/STAT5 pathway and/or the MAPK pathway in the
mammary glands and other target tissues (2, 3, 17). To gain insight
into the mechanism by which the lactogenic hormones stimulate mStaf
binding, the effects of various kinase inhibitors were examined. As
shown in Fig. 2, a MEK inhibitor, PD98059
(18), almost completely inhibited the hormonal stimulation of mStaf
binding, although this inhibitor had little effect on the hormonally
induced STAT5 binding (lane 3). On the other hand, a JAK inhibitor,
tyrphostin B42 (19), which reduced the enhancement of STAT5 binding by
the lactogenic hormones, did not affect the hormonal stimulation of
mStaf binding (lane 4). Although the direct effect of tyrphostin B42 on
the phosphorylation of JAK2 was not examined, these results suggest
that the MAPK, rather than the JAK/STAT, pathway is involved in mStaf
induction. Another kinase inhibitor, W7, which inhibits calmodulin
kinase activity (20), caused no detectable change in the binding of
either mStaf and STAT5 (lane 5).
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Figure 2. Effects of various kinase inhibitors on lactogenic
hormone-induced mStaf and STAT5 binding in cultured mouse mammary gland
explants. Mammary gland explants from virgin mice were cultured for
24 h with IHP in the presence or absence of kinase inhibitors,
PD98059 (PD; 100 µM), tyrphostin B42 (TB; 100
µM), and W7 (200 µM), as indicated. Five
micrograms of nuclear extracts from the cultured explants were used to
determine mStaf and STAT5 binding. U, Uncultured explants. The data
represent one of three independent experiments, which gave very similar
results.
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The effects of IHP and PD98059 on the level of mStaf mRNA in cultured
mammary explants were examined by Northern blot analysis. As shown in
Fig. 3A, mStaf mRNA was substantially
increased in a time-dependent manner by the triple hormone treatment
during 72-h culture (lanes 1–3), whereas the concomitant addition of
PD98059 inhibited the increase in mStaf mRNA (lane 4). A JAK inhibitor,
tyrphostin B42, had little effect on the level of mStaf mRNA (data not
shown).
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Figure 3. Northern and Western blot analyses of mStaf in
mouse mammary gland explants cultured with lactogenic hormones. Mammary
gland explants from virgin mice were cultured with IHP for 24 or
72 h or in the presence of IHP and 100 µM PD98059
for 24 h. A, Three micrograms of polyadenylated RNA from mammary
explants were electrophoresed, followed by Northern blot analysis as
described in Materials and Methods. B, Fifty micrograms
of nuclear extracts from mammary explants were subjected to SDS-PAGE,
followed by Western blot analysis as described in Materials and
Methods. U, Uncultured explants. The data in A and B represent
one of three independent experiments, which gave very similar
results.
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Western blot analysis of mammary nuclear extracts using specific
antibody against mStaf revealed the presence of 98-kDa mStaf protein
(Fig. 3B). The amount of this protein was increased by the triple
hormone treatment (lanes 1–3) and was reduced by the concomitant
addition of PD98059 (lane 4). It was present only in nuclear extracts,
not in cytosols, and was not detected by preimmunized control serum
(data not shown). These results together with those obtained by
Northern blot analysis suggested that the lactogenic hormones
stimulated mStaf binding at least in part by enhancing the levels of
both mStaf mRNA and protein through activation of the MAPK pathway.
As shown in Fig. 4, MAPK activity, which
was assayed by phosphorylation of myelin basic protein, was
undetectable in mammary explants at the beginning of culture, but
increased rapidly in response to IHP. The increase was detected as
early as 3 h, reaching a peak at 6 h. MAPK activity was still
substantially elevated at 24 h. No increase in MAPK activity was
found in explants cultured in the presence of PD98059 and IHP or in the
absence of the lactogenic hormones (data not shown).
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Figure 4. MAPK activity in mouse mammary gland explants
cultured with lactogenic hormones. Mammary gland explants from virgin
mice were cultured with IHP for 3, 6, or 24 h, and MAPK activity
was assayed as described in Materials and Methods. MBP,
Myelin basic protein; U, uncultured explants. The representative
results of five independent experiments are shown.
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IHP increases the amount of tRNASec
As mStaf was shown to serve as a transcriptional activator of the
tRNASec gene (14), we also examined the temporal change in
the level of tRNASec in mammary explants cultured with IHP
(Fig. 5). The level of
tRNASec in the triple hormone-treated explants increased in
a time-dependent manner during 72 h of culture, which followed the
increase in mStaf binding (cf. Fig. 1B). At 72 h, the
level of tRNASec was approximately 4.5-times higher than
that in uncultured or insulin-treated explants. On the other hand, the
amount of total RNA in the triple hormone-treated explants was
approximately 2.5 times higher than that in uncultured or
insulin-treated explants at 72 h (data not shown).
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Figure 5. Changes in mouse tRNASec level in
mouse mammary gland explants in culture. Mammary gland explants from
virgin mice were cultured with IHP (•) or insulin (I;  ) for
72 h. At the indicated times, total RNA was extracted, and the
amount of tRNASec was determined by Northern blot analysis.
The amount of tRNASec in explants cultured for the
indicated times was expressed per unit weight of tissue and presented
relative to that in the uncultured explants (U). The mean ±
SE values were obtained from three independent experiments.
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Discussion
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Recently, we cloned from mouse mammary gland a cDNA encoding
mStaf, a transcriptional activator of the mouse Pol III-dependent
tRNASec gene, and showed that mStaf enhances transcription
of the mouse tRNASec gene by cotransfection experiments in
Drosophila cells (14). In the present study, we employed
organ culture systems to investigate the regulation of mStaf binding
and its functional importance in tRNASec gene expression in
the mammary gland. Organ culture of the mammary gland has been useful
in delineating the hormonal determinants and their actions on the
cellular and molecular events associated with mammary gland
development. It has been established that the synergistic actions of
insulin, hydrocortisone, and PRL induce the functional differentiation
of mammary cells by inducing the expression of milk protein genes, such
as the ß-casein gene (21). Using this system, we found that the same
triple hormone combination increases the levels of mStaf binding and
tRNASec in cultured explants as was found in the case of
milk protein biosynthesis. These findings are consistent with the
developmental changes in mStaf binding and tRNASec in
vivo, suggesting that the increase in both mStaf binding and
tRNASec takes place as part of lactogenic processes to
accommodate the increased production of selenoproteins, such as
T4 5'-deiodinase and glutathione peroxidase, during the
period of lactation. It has been shown that the level of 5'-deiodinase
activity in human 293 cells is increased by transfection of plasmids
expressing tRNASec, suggesting that the level of
tRNASec is important for the regulation of selenoprotein
production (22).
PRL plays a key role in stimulation of the functional differentiation
of the mammary gland. It has been shown that PRL binds to its membrane
receptor and transmits its signal by several different pathways. For
example, activation of casein gene transcription is mediated by the
JAK/STAT pathway wherein PRL induces the phosphorylation of STAT5 by
activating JAK2, which serves as a transcriptional activator of the
casein gene (2, 3). PRL also has been shown to transmit its signal by
activating MAPK in HC11 mammary cells (17) as well as in Nb2 cells (23, 24). Our data revealed that MAPK activity in cultured explants was
induced rapidly by the lactogenic hormones, which preceded the increase
in mStaf binding. We also found that a MEK inhibitor, PD98059, inhibits
the hormone-dependent increase in the binding of mStaf, whereas a JAK
inhibitor or a calmodulin kinase inhibitor had no apparent effect.
These results suggest that the hormonal induction of mStaf involves the
MAPK pathway rather than the JAK/STAT pathway, which was used for
induction of STAT5 for casein gene transcription. Although MAPK
activity is hormonally induced in cultured mammary explants, mStaf may
not be a direct target of MAPK, because mStaf protein does not contain
the consensus motif, -P-X-S/T-P- (25, 26), for MAPK phosphorylation.
Moreover, mStaf protein produced by an in vitro reticulocyte
translation system was capable of binding to the AE region without
being phosphorylated (our unpublished data). Thus, it appears that the
PRL-dependent increase in mStaf binding is not mediated by MAPK
phosphorylation of mStaf itself.
Northern and Western blot analyses indicated that the levels of mStaf
mRNA and protein in mammary explants were increased by lactogenic
hormones and were reduced by the concomitant presence of the MAPK
inhibitor. Thus, these results are in accord with those obtained by
EMSA, suggesting that the alterations in mStaf binding are at least in
part due to the change in the level of mStaf mRNA and protein. At the
present time, however, the mechanism by which the lactogenic hormones
regulate the biosynthesis of mStaf protein via the MAPK pathway remains
to be elucidated.
Comparison of the results obtained by EMSA and Western blot analyses
revealed some notable differences between the levels of mStaf binding
and protein. For example, mStaf binding in uncultured explants was
virtually undetectable, although the presence of mStaf protein in these
explants was apparent by Western blot analysis. Moreover, the results
obtained by EMSA apparently gave a larger magnitude of increase in the
mStaf level of the triple hormone-treated explants compared with those
by Western blot analysis. It is possible that some of these differences
are due to the difference in the sensitivity of the two assays.
However, it is also possible that the observed discrepancy between the
levels of mStaf binding and protein is indeed real. It is conceivable
that the binding activity of mStaf is influenced by some modification
of the protein or by some unidentified factors.
Northern blot analysis of tRNASec indicated that IHP
increases the transcript in a time-dependent manner, which was preceded
by the increase in mStaf-binding activity in cultured mammary tissue.
Thus, these data strongly support the view that lactogenic hormones
stimulate tRNASec transcription by increasing the amount of
mStaf binding, which enhances transcription of the tRNASec
promoter by binding to the AE region.
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Acknowledgments
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We thank Drs. Deborah M. Hinton, Karen Usdin, and Michael D.
Davis for their discussion and critical reading of our manuscript.
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Footnotes
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1 Present address: Molecular Biology Department, Nippon Shinyaku Co.
Ltd., 3–14-1 Sakura, Tsukuba-City, Ibaraki 305, Japan. 
2 Present address: Department of Medicine III, Osaka University
Medical School, 2–2 Yamada-oka, Suita-City, Osaka 565, Japan.
Received August 17, 1998.
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Abstract
Introduction
