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U-488 INSERM-Unité de Recherche Stéroïdes et Système Nerveux (S.P., M.R., J.-M.G., A.-M.L., N.M., M.P., F.C.), 94276 Le Kremlin Bicetre Cedex, France; and the Departments of Medicine and Physiology, Dartmouth Medical School (D.L.S.), Lebanon, New Hampshire 03756
Address all correspondence and requests for reprints to: Dr. Françoise Courtin, U-488 INSERM-Unité de Recherche Stéroïdes et Système Nerveux, 94276 Le Kremlin-Bicêtre Cedex, France.
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Abstract |
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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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Complementary DNAs (cDNAs) for the D2 and D3 from several mammalian species have recently been isolated and shown to code for proteins containing the uncommon amino acid selenocysteine at the active catalytic site (4, 5, 6). The importance of selenium for deiodination in astroglial cells has recently been demonstrated; the expression of both D2 and D3 in these cells is markedly impaired by selenium deprivation (7, 8). Factors that alter cellular processes through signaling cascades originating at the plasma membrane have been demonstrated also to have important effects on the levels of deiodinase activity in these cells. For example, D3 activity is markedly and rapidly induced by 12-O-tetradecanoyl phorbol-13-acetate (TPA) and by acidic and basic fibroblast growth factors (aFGF and bFGF, respectively) (9). Other growth factors (e.g. epidermal growth factor and platelet-derived growth factor) as well as cAMP analogs and forskolin have significant, although quantitatively lesser, stimulatory effects on glial cell D3 activity (9). In addition, ligands for certain nuclear receptors, most notably retinoic acid (RA) and thyroid hormones, have important effects on D3 activity levels (10, 11).
Only limited information is available concerning the mechanisms of D3 regulation. Recently, the induction of D3 messenger RNA (mRNA) levels by various growth factors in primary cultures of rat brown adipocytes has been described (12). However, the effects of these and other agents on D3 transcript levels in the central nervous system have not been reported, nor is it known what pathways mediate the TPA- and growth factor-induced stimulation of this enzyme. TPA is known to initiate signaling by activation of certain protein kinase C (PKC) isoforms, whereas FGF’s effects are mediated through activation of its receptor’s tyrosine kinase (13). These proximal events, in turn, stimulate several intracellular signaling cascades. A downstream pathway induced by both TPA and growth factors in astrocytes and other cell systems is the Raf/MEK/Erk cascade (14, 15). This pathway is responsible for the phosphorylation of many target proteins in response to stimulation by mitogens and growth factors and has been shown to be involved in the regulation of several genes (16, 17, 18, 19). In particular, the Raf/MEK/Erk cascade has been documented to alter gene expression through effects on transcription from the serum response element (20).
In the present studies, we have examined the effects of T3, RA, TPA, and bFGF on the expression of D3 mRNA in cultured astroglial cells. Furthermore, we provide evidence that the MEK/Erk signaling cascade is probably an important mediator of D3 induction by TPA and bFGF.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]ATP (3 Ci/mmol), and the Megaprime
DNA Labeling System were purchased from Amersham
(Aylesbury, UK). [
-32P]Deoxy (d)-CTP (3000 Ci/mmol)
was obtained from DuPont de Nemours (Les Ulis, France). Sprague Dawley
rats were purchased from Iffa-Credo (L’Albresle, France). FCS and
culture media were obtained from Life Technologies (Grand
Island, NY), and culture dishes were obtained from Nunclon (Roskilde,
Denmark). Biotrans Nylon membranes were obtained from ICN (East Hills,
NY). Oligo(deoxythymidine)-cellulose was purchased from Collaborative
Biomedical Products (Bedford, MA). QIAquick Gel Extraction Kit was
obtained from QIAGEN (Chatsworth, CA). Recombinant
ribonuclease inhibitor was obtained from Promega Corp.
(Madison, WI), Moloney murine leukemia virus (MMLV) reverse
transcriptase was obtained from Life Technologies, and the
Expand High Fidelity PCR System was purchased from Boehringer Mannheim (Mannheim, Germany).
Cell culture conditions
Brains were removed from 2-day-old Sprague Dawley rats and
cleaned of meninges and blood vessels. Two cerebral hemispheres were
then dissociated to form a cell suspension by passage through a nylon
mesh (82-µm pore size) into 40 ml DMEM supplemented with 6 g/liter
glucose, 2.4 g/liter sodium bicarbonate, antibiotics (100 U/ml
penicillin, 100 µg/liter streptomycin, and 0.25 µg/liter
amphotericin), and 10% FCS (DMEM-FCS). Aliquots (3 ml) of
this cell suspension were placed in 60-mm petri dishes, and the
cultures were maintained at 37 C under 5% CO2-95% air and
more than 90% humidity. The medium was changed every 2–3 days until
cells reached confluence at about 10 days. At this stage, the DMEM-FCS
was removed, and the cells were washed with a chemically defined medium
(a 1:1 mixture of DMEM and Ham’s F-12 medium (DMEM/F12) supplemented
with 5.2 g/liter glucose, 1.8 g/liter sodium bicarbonate, and the
antibiotics listed above). The cells were then cultured for 3
additional days in DMEM/F12 supplemented with 30 nM sodium
selenite, 10 µg/ml insulin, and 10 µg/ml transferrin followed by 1
additional day in DMEM/F12 supplemented with 30 nM sodium
selenite, 1 µM cortisol, and 10 µg/ml transferrin.
Under these culture conditions, 95% of the cells contain
immunoreactive glial fibrillary acidic protein (11), a specific marker
of astrocytes. Cultured astrocytes were treated with the test agents
for the times and at the concentrations indicated in each
experiment.
Cell harvesting and D3 assay
At the time of harvesting, the medium was aspirated, and the
cells were rinsed twice with 3 ml ice-cold PBS. Culture dishes
containing the cells were then frozen at -80 C for later processing
and analysis. This involved placing the plates on ice, scraping the
content of each dish into 0.4 ml sample buffer (20 mM
HEPES, 2 mM DTT, and 0.25 M sucrose, pH 7.4), and
disrupting the cells by sonication. D3 activity was measured by
incubating aliquots of the cell sonicate (containing 4–40 µg
protein) in an 80-µl final volume of 20 mM HEPES buffer,
pH 7.4, containing 20 mM DTT and 5 nM
[125I]T3 for 20–60 min at 37 C. Reactions
were stopped by adding 10 µl 10 M NH4OH
containing 10 µM T3 and 10 µM
T4. The [125I]3,3'T2 produced was
separated from [125I]T3 by descending paper
chromatography (21). Deiodination was linear with both protein and
time, and the quantity of protein assayed was adjusted to ensure that
less than 30% of the substrate was consumed. Data represent the mean
from either two or three dishes ± SD. D3 activity
assays were repeated in three separate experiments.
RNA preparation and Northern analysis
RNA was prepared from cultured glial cells by the method of
Chomczynski and Sacchi (22). Polyadenylated RNA was isolated by one
cycle of chromatography over oligo(deoxythymidine)-cellulose. Northern
analysis was performed using methods previously described (23). In
brief, Northern blots were hybridized overnight at 42 C in 15 ml
hybridization buffer [50% deionized formamide, 5 x
saline-sodium phosphate-EDTA buffer (pH 7.4), 0.1% SDS, and 5 x
Denhardt’s solution] containing 100 µg/ml salmon sperm DNA and 1.5
million cpm/ml cDNA probe. The final wash was performed at 60 C for 60
min in 0.1 x SSC-0.1% SDS. After hybridization and analysis with
the D3-specific probe, blots were stripped and reprobed with a rat
ß-actin probe. Hybridization signals were quantified by densitometry,
and the ratio of D3 to ß-actin mRNA was calculated.
The D3 cDNA probe was prepared by EcoRI digestion of the plasmid containing the rNS27–1 rat D3 cDNA (4). This generated a 1562-bp fragment that contains the majority of the coding region and the 3'-untranslated region of the D3 mRNA. The fragment was separated on low melt agarose gel and stained with ethidium bromide; the appropriate band was excised and then labeled with 32P.
Erk [mitogen-activated protein (MAP) kinase] assay
Erk (MAP kinase) activity was measured by incubating 5 µl
astrocyte extract, prepared as previously described (14, 24), for 10
min at 30 C in a final volume of 50 µl containing 20 mM
HEPES (pH 7.4), 5 mM MgCl2, 2 mM
EGTA, 2 mM DTT, 1 mM
Na3VO4, 20 µM
[-32P]ATP (3 Ci/mmol), 17 µg myelin basic protein,
and 10 µg/ml of the protein kinase A peptide inhibitor. The reaction
was initiated by adding an aliquot of the extract and was stopped by
spotting 40 µl of the reaction mixture onto Whatman 3MM
paper (Whatman, Clifton, NJ). The papers were washed once
with 10% trichloroacetic acid containing 3 mM ATP (for at
least 1 h) and three times with 5% trichloroacetic acid, dried
with ethanol-ether and then ether alone, and finally counted for
radioactivity.
RT-PCR assay
RT-PCR was used in some experiments to study the induction of D3
mRNA. RT was performed with 50, 100, and 200 ng total RNA for each
sample in a 20-µl reaction volume containing 1 mM DTT,
0.5 mM dNTP mix, 1 µM of random primers, 200
U recombinant ribonuclease inhibitor, 1 x first strand buffer,
and 200 U MMLV reverse transcriptase. After a 1-h incubation at 42 C, 5
µl of each RT mixture were used for the PCR. The PCR reaction was
performed in 50 µl containing 0.2 mM dNTPs, 0.1 µCi
[-32P]dCTP, 0.4 µM of sense and
antisense primers (see sequence below), 2.6 U Expand High Fidelity PCR
System, and 1 x Expand High Fidelity buffer containing 1.5
mM MgCl2. Thirty cycles of PCR were employed,
with an annealing temperature of 64 C. The oligonucleotide primers were
derived from the coding region of the rat D3 cDNA. These were: sense,
5'-CCCTGCTGCTTCACTCTCTG-3'; and antisense, 5'-GGTCCCTTGTGCGTAGTCGA-3'.
An amplification product of 386 bp was expected. Products were
separated on an 0.8% agarose gel and transferred to a nylon membrane,
and the quantity of radiolabeled nucleotide incorporated was determined
using the Instant Imager (Packard Instrument Co.,
Meriden, CT) analysis. For each sample, the quantity of PCR
product derived was a linear function of the initial amount of RNA
added over the range examined (50–200 ng). Control PCR reactions using
as template 5 µl reverse transcriptase mixtures lacking either RNA or
MMLV yielded no product. The integrity of the RNA samples used in the
RT-PCR reactions was demonstrated by observing intact 18S and 28S
ribosomal RNA bands on agarose gel electrophoresis.
As an additional control, another PCR amplification was performed on each sample using a 5- or 2.5-µl aliquot from the 50-ng reverse transcriptase mixture and oligonucleotide primers derived from the S26 ribosomal protein sequence (sense, 5'-GTGCGTGCCCAAGGATAAGG-3'; antisense, 5'-ATGGGCTTTGGTGGAGGTCG-3') (25). An amplification product of 261 bp was expected. PCR conditions and the methods of product analysis were the same as described above.
Protein determination
The protein content of cell sonicates was determined by the
method of Bradford (26) using BSA as standard.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The induction of D3 activity by both 10 nM T3
(Fig. 1
) and 1 µM RA (Fig. 2A) was relatively slow; activity
progressively increased for 48 h after treatment with these
agents. In contrast, a marked increase in D3 activity was noted by
7 h in cells treated with 100 nM TPA (Fig. 2A). D3
mRNA also increased after 24 and 48 h of T3 and RA treatment.
These levels, however, were significantly less than those noted in the
cells treated with TPA despite the fact that RA and TPA induced D3
activity to a comparable extent in this experiment. To verify that RA
does stimulate D3 mRNA, glial cell total RNA was subjected to RT-PCR, a
more sensitive method of RNA analysis. Using this technique, an
increase in D3 transcript levels was noted as early as 2 h after
exposure to RA, and this persisted for 24 h (Fig. 2B). This was a
consistent finding in several experiments, although the results cannot
be evaluated in a strictly quantitative fashion using the RT-PCR
technique that was employed (27).
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, T3 and
TPA were noted to have synergistic effects on stimulating both D3
activity and mRNA levels; preincubating astrocytes for 24 h with
10 nM T3 markedly potentiates the stimulatory
effect of 100 nM TPA. The time course of this inductive
effect is shown in Fig. 4 where cells
were preincubated with 10 nM T3 for 24 h
and then stimulated with TPA and harvested immediately or 2, 5, 7, or
12 h later. Consistent with our prior results (9), a small
increase in D3 activity was noted at 5 h after TPA addition,
whereas a marked increase to near-maximal levels was noted at 7 h
(Fig. 4A). Stimulation of D3 mRNA levels appeared to precede the rise
in enzyme activity; Northern analysis detected an increase in
transcript levels at the 2 h point and a strong induction by
5 h (Fig. 4B). Transcript levels appeared to peak at 7 h and
then markedly declined, such that at 12 h, the D3 mRNA level had
nearly returned to that noted in the basal state. However, D3 activity
was still high at this time point, suggesting that the D3 protein is
relatively stable in cultured astrocytes. This inference is consistent
with our prior observations (7).
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where both D3
activity and mRNA are shown to be markedly elevated after treating
astroglial cells with this growth factor for 7 h. In addition, the
stimulatory effects of T3 and bFGF on D3 activity and mRNA
appeared to be greater than additive, as was the case with
T3 and TPA. Of interest in Fig. 5 is the finding that D3
activity was induced to similar levels by treatment of cells with
either T3 for 24 h or with bFGF for 7 h. However,
the induction of D3 mRNA was much less with the former agent. This is
similar to the finding presented in Fig. 2A
that very modest levels of
D3 mRNA induction by RA were accompanied over a period of 24–48 h by a
large increase in D3 activity.
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, ß1, ß2, and ) (28, 29). PD 98059 is a
specific inhibitor of the Erk-activating kinase (MEK) when used at
concentrations below 50 µM (30).
When astrocytes were preincubated for 30 min with relatively low
concentrations (1 µM) of GF 109203X, induction of D3
activity by 100 nM TPA was almost completely blocked (Fig. 6A). This finding is consistent with the
effects of TPA on D3 induction being mediated through classical PKC
isoforms. In contrast, stimulation of D3 activity by bFGF was impaired
by only 30% in the presence of 1 µM GF 109203X. At
higher concentrations of this inhibitor (5 µM), a greater
degree of inhibition (
70%) was noted (Fig. 6B). That these
inhibitory effects of GF 109203X were not due to nonspecific toxicity
was demonstrated in other studies in which the treatment of cells with
this agent did not impair the induction of D3 activity by
cAMP-stimulating agents such as forskolin (Pallud, S., and F. Courtin,
unpublished data).
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. A
marked inhibition of induction of both D3 activity and mRNA levels by
TPA (Fig. 7A) and bFGF (Fig. 7B) was noted. This inhibitory effect also
occurred if the pretreatment period with PD 98059 was extended to
24 h (data not shown).
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These findings suggested that the MEK/Erk cascade is a downstream
transducer of both the TPA and bFGF stimulatory effects on D3. To
further implicate this pathway, Erk (MAP kinase) activity was
determined in astroglial cells after exposure to TPA and bFGF. As shown
in Fig. 8, these agents induced a 3- to
4-fold increase in MAP kinase activity, an effect that was largely
blocked by pretreatment of cells with 30 µM PD 98059.
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. In control unstimulated astroglial
cells, treatment with PD 98059 for 24 h resulted in a small
increase in D3 activity from the low basal levels present in these
cells. This effect, however, was not seen in short term (8 h)
incubations (see Fig. 6). The addition of RA or T3 to the
cultures stimulated a large increase in D3 activity after 24 h, as
noted previously, and this effect was enhanced an additional 3-fold in
cells treated with PD 98059. This potentiation by PD 98059 of the
stimulatory effects of RA and T3 was observed in two additional
experiments.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The compounds tested use distinct signaling mechanisms. This may account for the differences in the degree and rate of D3 induction that were observed with these agents. Thus, compounds that generate signals from the cell surface (i.e. TPA and bFGF) induced rapid increases in D3 mRNA and activity, whereas treatment with ligands that interact with nuclear receptors (T3 and RA) result in slower effects. Under all conditions, however, the increase in D3 mRNA levels suggests that pretranslational mechanisms mediate at least in part the induction of D3 activity. Such mechanisms are consistent with the known effects of these growth factors and ligands on altering rates of gene transcription (31, 32), although other mechanisms affecting mRNA stability could be involved.
The synergistic effects of T3 with TPA or bFGF on stimulating D3 mRNA and activity are striking, and we are not aware of other instances where this has been described for this combination of reagents. The mechanism(s) responsible for this effect is uncertain, but could involve synergistic effects on activating transcription, stabilization of D3 mRNA by T3, as has been demonstrated for several other mRNAs (33, 34, 35), or T3-induced alterations in the MEK/Erk cascade. Information concerning the latter possibility has not been published previously; however, we have recently demonstrated that T3 and RA do not activate Erk in cultured astrocytes during an 18-h incubation (Munsch, N., and M. Pierre, unpublished observations).
An additional finding in these studies was the transient nature of the D3 mRNA induction by TPA; levels peaked at 7 h of treatment and had nearly returned to baseline by 12 h. Such short-lived effects were not noted after T3 or RA treatment, conditions in which mRNA levels progressively increased for 48 h. This protracted increase in D3 mRNA along with the relatively long half-life for the D3 protein may explain in part why D3 activity progressively increases to quite high levels during 48 h of treatment with T3 or RA despite the finding that these agents induces relatively small increases in mRNA levels. Alternatively, this dichotomy may reflect alterations in posttranslational processes.
Our finding that 1 µM GF 109203X almost completely blocks the induction of D3 by TPA implicates PKC isoforms as the principal upstream mediators of the effect of this agent. In contrast, induction by bFGF was only partially inhibited by GF 109203X, even at higher concentrations. This suggests that pathways not involving classical PKC isoforms are probably involved in D3 induction by bFGF, a finding consistent with the known mechanism of action of this growth factor to activate its receptor tyrosine kinase (13). With both TPA and bFGF, however, downstream activation of the MEK/Erk cascade appears to be essential for D3 induction. This conclusion is based on the observations that 1) TPA and bFGF at doses that induce D3 expression also activate Erk; and 2) PD 98059 at relatively low concentrations significantly impairs the inductive effects of these agents. Of importance, others have demonstrated the high degree of specificity of PD 98059 for inhibiting MEK; at the concentrations used in our studies, this compound does not inhibit Raf kinase, cAMP-dependent kinase, PKC, v-Src, phosphatidylinositol 3-kinase, or a number of growth factor receptor kinases (30). However, our finding that PD 98059 only partially inhibits D3 induction may imply that pathways other than MEK/Erk also play a role in the stimulatory effects of mitogens and growth factors. Alternatively, this partial inhibition may have been secondary to the relatively low concentrations of PD 98059 used in our studies.
A striking and consistent 3- to 4-fold increase was noted in the stimulatory effects of T3 and RA on D3 activity in the presence of PD 98059. This suggests that the MEK/Erk cascade may, under basal conditions, limit the inductive effects of these nuclear ligands on D3 expression. However, given that the experiments with T3 and RA involved treatment with PD 98059 for 24 h, the potentiating effects of this compound on D3 activity could have been mediated by secondary alterations in other signaling pathways rather than direct inhibition of MEK/Erk activity. Thus, additional studies will be needed to determine the molecular mechanisms responsible for these effects and their physiological significance.
In summary, multiple hormones and growth factors control D3 expression in astroglial cells. Combined with the previously described intricate patterns of regulation of the D2 (36, 37, 38), a picture emerges in which the control of T3 levels in neural tissue represents an integrated response to a complex array of signals. Although whole animal studies have demonstrated the importance of thyroid status in regulating brain deiodinase activities (3, 39, 40), the present experiments add to the accumulating evidence that other physiological factors under appropriate circumstances may impact thyroid hormone economy in this tissue.
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Footnotes |
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Received September 11, 1998.
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