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Department of Medicine, Division of Endocrinology and Metabolism, University of California-San Diego, La Jolla, California 92093-0618; and the Department of Internal Medicine, University of Heidelberg (R.H.), Heidelberg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1- vs.
T3Rß1-specific interactions with the myocyte
enhancer-specific factor-2 (MEF-2) on the expression of the SERCA 2
gene in transient transfection assays in embryonal heart-derived H9c2
cells. MEF-2a in combination with either T3R1 or
T3Rß1 isoforms resulted in a 2.5-fold increase in SERCA 2
transgene expression in the absence of T3. Addition of
T3 did not induce any further increase in SERCA 2
expression when T3R1 and MEF-2a expression vectors were
cotransfected. In contrast, in the presence of T3Rß1 and
MEF-2, the addition of T3 increased chlorampenicol
acetyltransferase activity by an additional 2.2-fold to a total
5.5-fold increase. The interaction between MEF-2a and T3R
is transcription factor specific because another factor that binds to
MEF-2 consensus sites (heart factor 1b) was not able to interact with
T3R. In addition, MEF-2a failed to interact with other
nuclear factors (cAMP response element-binding protein and Egr-1) that
stimulate SERCA 2 gene transcription. In addition, we found that a
single homologous thyroid hormone response element is not able to
mediate the interactions between MEF-2a and T3Rs to
increase SERCA 2 gene transcription. Our findings point to
T3R isoform-specific interactions with a cell type-specific
transcription factor (MEF-2) in the regulation of SERCA 2 gene
expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(MHC) have been reported (3, 5). Details of the transcriptional
regulation of cardiac genes by T3 remain unexplored. It is,
for example, unclear whether interactions between transcription factors
that are important in regulating the myocyte-specific gene program,
such as myocyte enhancer-specific factor-2a (MEF-2a) (6) and
T3 receptors (T3Rs) occur. In addition, it is
currently unclear whether the simultaneous occurrence of different
T3R isoforms, in particular T3R1 and
T3Rß1, in cardiac myocytes serve T3R
isoform-specific regulatory functions. Previous studies, focusing on
the central nervous system, showed that messenger RNAs coding for
different T3R isoforms are differentially expressed in a
developmental and spacial fashion, suggesting that T3R
isoforms probably exhibit distinct functions (7). Furthermore, there is
evidence, from T3Rß knock-out mice, that the
T3Rß isoform is necessary for inner ear development. This
is a function that cannot be assumed by T3R1 (8).
Functional analyses of T3Rs have shown that they contain
two types of transcription activation functions (AF). The AF2, mediated
by the carboxyl-terminal D/E/F domain has been strictly associated with
hormone-dependent transactivation (9). The domain D/E/F is well
conserved among the T3R isoforms, and the ligand-dependent
transactivation function mediated by this domain is similar as well
(10). On the other hand, the AF1 function, mediated by the N-terminus
A/B domain, has been reported as having both ligand-dependent and
independent transactivation properties and is, at the moment, the less
well understood activation activity (9, 11). Furthermore, this domain
presents no significant amino acid sequence similarity among the
T3R isoforms able to bind ligand, suggesting that the
N-terminus probably mediates T3R isoform-specific actions.
We used the gene coding for the Ca2+ ATPase of the
sarcoplasmic reticulum as a model for studying interactions between
T3Rs and the MEF-2a transcription factor. SERCA 2 plays an
important role in heart function by lowering free cytosolic calcium
levels during diastole, and T3-induced increases in the
speed of diastolic relaxation in the heart are largely mediated through
increased expression of this gene (12, 13, 14). In addition, we identified
three thyroid hormone response elements (TRE) located in the regulatory
region of the SERCA 2 gene (4). TRE1, localized at nucleotides -481 to
-458, is a direct repeat element spaced by four nucleotides; TRE2, at
-310 to -289, is an inverted palindrome spaced by four nucleotides,
and TRE3, at -219 to -195, is an inverted palindromic element spaced
by six nucleotides. MEF-2a is a transcription factor very important for
myogenesis, and its high expression is maintained throughout
development (6); therefore, it is likely that this factor modulates
gene transcription in genes such as SERCA-2. MEF-2 was originally
described as a muscle-specific transcription factor that recognizes
A/T-rich elements that occur in genes expressed in striated muscle
cells (15). Analysis of the regulatory region of the gene coding for
creatine kinase M led, initially, to identification of the MEF-2a
transcription factor and a MEF-2 consensus binding site (15).
Subsequent work revealed that the MEF-2 factor belongs to the family of
MADS motif-containing transcription factors (6). Separate genes coding
for MEF-2a, MEF-2b, MEF-2c, and MEF-2d, each of which have several
different splice variants, making for a complex family of MEF-2 factors
(6, 16, 17, 18, 19, 20, 21). An important role for MEF-2 in determining muscle cell
lineage was demonstrated by forced expression of MEF-2 in fibroblasts,
resulting in muscle differentiation (21).
Our results indicate that an interaction that is more than additive
occurs between MEF-2a and T3R1 or T3Rß1 in
the absence of T3. In the presence of T3, a
T3 isoform-specific interaction with MEF-2 occurs with only
T3Rß1, leading to a further increase in transgene
expression. Different T3R isoforms may, therefore, play an
isoform-specific role in interacting with cell type-specific
transcription factors, allowing for cell type-specific modifications in
the regulation of T3-responsive genes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 (3, 6, and
9 µg), T3Rß1 (3 µg), MEF-2a (5 µg), cAMP responsive
element-binding protein (CREB; 3 µg), a constitutively active protein
kinase A (PKA; 3 µg), Egr-1 (7 µg), and heart factor 1b (HF-1b; 4
µg) and a plasmid containing SERCA 2 regulatory region linked to the
chloramphenicol acetyl transferase (CAT) reporter gene (3.2 SERCA 2
CAT; 7 µg). The final amount of DNA was 20 µg/plate and was
obtained by adding plasmid pBS (Stratagene, La Jolla, CA). After
transfection, cells were washed twice with serum-free medium and
thyroid hormone-free serum-containing medium was then added. Plates
were treated when necessary with T3 at a final
concentration of 10-7 M.
Harvest of cells and enzymatic assays
Twenty-four hours after T3 treatment, cells were
washed twice with PBS and harvested in 150 µl 0.25 M Tris
(pH 7.8). Cells were lysed by three cycles of freezing for 5 min (dry
ice in methanol) and thawing (37 C) for 3 min. Cellular extracts were
pelleted, and supernatants were collected and aliquoted to determine
the activity of ß-galactosidase (25) and CAT (26). CAT activity was
determined by TLC and autoradiography. Spots containing differently
acetylated [14C]chloramphenicol were removed from the
thin layer plates, and radioactivity was determined by liquid
scintillation counting.
Expression plasmids
Expression plasmids containing 3.2 kilobases (kb) of the
upstream regulatory elements of the SERCA 2 gene fused to the bacterial
gene coding for CAT were constructed as previously described (3). In
brief outline, approximate restriction fragments of the SERCA 2
regulatory region were obtained by digestion of SERCA 2 genomic
fragments in a 
DASH clone (/SERCA 21). This construct is
designated 3.2 SERCA 2 CAT because it contains 3.2 kb of SERCA 2
regulatory region 5' from the transcription start site. To generate a
construct in which TRE1 was linked to the thymidine kinase (TK)
promoter and CAT, a reporter clone containing 0.6 kb of SERCA 2
regulatory region termed pGCCAT0.6 was digested with appropriate
restriction enzymes, creating a region encompassing -490 to -350
relative to the start site of transcription of the SERCA 2 gene. TRE1
was located in this region (4). HindIII and BamHI
sites were created at the 5'- and 3'-ends, respectively, by ligation of
linkers to previously blunt-ended fragments. This fragment was then
cloned into a TK promoter-containing vector (pBLCAT2) (27) previously
digested with HindIII and BamHI. The
ß-galactosidase expression plasmid is driven by the cytomegalovirus
(CMV) enhancer/promoter. This plasmid was used in the experiments as a
control for transfection efficiency and squelching. The expression
plasmids for the rat T3R1, T3Rß1, and a
rat T3Rß1 N-terminal deletion mutant (amino acids 4–89)
designated NMT3Rß1 are driven by the CMV promoter, these
clones were kindly provided by Dr. H. Towle, University of Minneapolis
(Minnesota, MN). The expression clone for Egr-1 is driven by the CMV
promoter (provided by Dr. E. Adamson, La Jolla Cancer Institute, San
Diego, CA). Expression vectors for the constitutively active PKA and
CREB were provided by Dr. Montminy (The Salk Institute, San Diego, CA).
The vector expressing HF-1b was provided by Dr. Chien (University of
California-San Diego) (20). The human MEF-2a expression plasmid was
provided by Dr. Nadal-Ginard (Harvard Medical School, Boston,
MA).
Experimental animals
All animal experimentation described in this manuscript were
conducted in accordance with the highest standards of humane animal
care, as outlined in the Guidelines for Care and Use of Experimental
Animals.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 or MEF-2a
individually (Fig. 1a
). No significant change in
reporter activity above baseline levels occurred. Similarly, treatment
of H9c2 cells, previously transfected only with the 3.2 SERCA 2 CAT
construct, with T3 (10-7 M) did
not alter the basal expression of reporter gene (Fig. 1a). On the other
hand, cotransfection of both T3R1 and MEF-2a expression
plasmids resulted in a 2.5-fold increase in reporter activity above
baseline levels in the absence of T3. The addition of
T3 (10-7 M) did not lead to a
further increase in reporter activity when T3R1 and
MEF-2a expression plasmids were used.
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1 expression vector and obtained fairly similar
results in the absence of T3, but strikingly different
results in the presence of T3 (Fig. 1b
). Cotransfection of
expression vectors for either T3Rß1 or MEF-2a
individually did not induce any increase in CAT expression. Again in
line with results using T3R1, cotransfection of
T3Rß1 and MEF-2a expression vectors induces a 2.5-fold
increase in CAT expression characterizing an interaction between
T3Rß1 and MEF-2a. In contrast to experiments with
T3R1, when T3Rß1 expression plasmid was
used in combination with MEF-2a expression plasmid and T3,
an additional 2.2-fold increase in reporter activity occurred in
addition to the 2.5-fold increase induced by T3Rß1 and
MEF-2a in the absence of T3, leading to a total 5.5-fold
increase in reporter activity. Interestingly, when H9c2 cells were
cotransfected with MEF-2a and NMT3Rß1 (expresses an
N-terminus-deleted T3Rß1) vectors and subsequently
treated with T3, only a 3-fold increase in CAT reporter
activity was observed. These results demonstrate that the
T3Rß1 N-terminus mediates the ligand-dependent
MEF-2a/T3Rß1 interaction. In addition, we tested the
possibility that the differential ligand-dependent transactivation
activity of the T3R isoforms in the presence of MEF-2a
might be due to a more efficient transcription of the vector expressing
T3Rß1 (compared to T3R1). H9c2 cells were
cotransfected with the 3.2 SERCA 2 CAT construct, expression vector for
MEF-2a, and increasing amounts of the expression vector for
T3R1 (6 and 9 µg/plate). Cells were subsequently
treated with T3 when necessary. As shown in Fig. 2, even high amounts of T3R1 were not
able to induce the T3 isoform-specific interaction observed
when T3Rß1 and MEF-2a expression plasmids were
cotransfected followed by treatment with T3. These data
indicate that the phenomenon observed is restricted to
T3Rß1 and, therefore, is not due to different levels of
T3R isoforms in transfected cells. Only interaction of
T3Rß1, and not of T3R1, with
T3 in the presence of MEF-2a, therefore, led to a further
increase in SERCA 2 gene transcription.
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, cotransfection of CREB plus PKA expression plasmids induced reporter
activity 2.2-fold. The addition of MEF-2a to PKA and CREB in
cotransfection experiments did not further increase reporter activity.
Therefore, MEF-2a does not, under these conditions, interact with the
CREB/PKA factor.
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and show that cotransfection of Egr-1 expression
vector promotes a 10-fold increase in SERCA 2 CAT activity. When Egr-1
and MEF-2a expression plasmids are cotransfected, no significant
further increase in reporter activity occurs, indicating no significant
MEF-2a/Egr-1 interaction.
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1 and HF-1b. Similar to the results presented in Fig. 1a, cotransfection of T3R1 expression vector did not
alter the baseline reporter activity of 3.2 SERCA 2 CAT construct (Fig. 5). Treatment of the cells, previously transfected with
expression vector for T3R1, with T3 induced
a 3-fold increase in reporter activity. Cotransfection of HF-1b
expression vector induced a modest increase in CAT expression of
1.8-fold. When HF-1b and T3R1 expression plasmids were
cotransfected, there was a 1.65-fold increase in reporter activity,
very similar to the induction obtained by HF-1b alone. In addition,
when H9c2 cells cotransfected with expression vectors for HF-1b and
T3R1 were treated with T3, there was a
3.2-fold increase in CAT expression. This is a response that is not
different from that achieved with T3 and T3R in
the absence of MEF-2a. These results, therefore, indicate that another
factor (HF-1b), which binds to A/T-rich elements, cannot assume the
role of MEF-2a and, therefore, exhibits a unique role in interacting
with T3R.
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1 and
MEF-2 into H9c2 cells, which were maintained in the presence or absence
of T3. As shown in Fig. 6, cotransfection of
the TRE1 TK CAT vector with expression vector for T3R1
induced a 60% decrease in CAT expression in the absence of
T3. Similar results were obtained when the
T3Rß1 expression plasmid was used (data not shown).
Treatment with T3 increased reporter activity about 3-fold,
confirming previous data obtained by us showing that this TRE is
functional. Cotransfection of the TRE1 TK CAT plasmid and the
expression plasmid for MEF-2a did not result in increased reporter
activity. Furthermore, cotransfection of expression plasmids for
T3R1 and MEF-2a did not increase reporter activity of
the TRE1 TK CAT construct. These results are in striking contrast to
those obtained with the 3.2 SERCA 2 CAT vector. Addition of
T3 to H9c2 cells cotransfected with the TRE1 TK CAT vector,
MEF-2a and T3R1 expression plasmids resulted in an
approximately 3-fold increase in CAT expression. These results most
likely indicate that the MEF-2a/T3Rs interaction can only
lead to optimal activation of transcription when both a TRE for
T3R binding and MEF-2-binding elements for MEF-2 attachment
occur in the regulatory region of a T3-responsive gene such
as SERCA 2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1 or
T3Rß1 leads to a 2.5-fold transactivation. Moreover, the
addition of T3 leads to additional SERCA 2 transactivation
only in the presence of T3Rß1. Modification of
T3 nuclear receptor-based transcription effects by other
nuclear factors have been well described (10, 31, 32, 33, 34). For example,
retinoid X receptor (RXR) forms heterodimers with T3R and
markedly increases the affinity of the complex for the TRE and in this
way enhances the effects of T3 (10). In contrast, the
fos and jun transcriptional factors inhibit
T3R activity; jun especially is able to inhibit
the binding of T3R to the TRE (35, 36, 37). The mechanism by
which MEF-2a interacts with either T3R1 or
T3Rß1 leading to the transactivation of SERCA 2 transgene
is currently unclear, but it appears unlikely that this occurs through
a mechanism similar to that for the RXR-T3R interaction.
The RXR/T3R heterodimer binds with higher affinity to TREs
than T3R homodimers (3, 10). RXR can, therefore, induce
increased binding and transactivation effects of T3Rs to
influence SERCA 2 transactivation when only one TRE is placed upstream
of a basal promoter. On the other hand, MEF-2a, in the presence of
T3Rs, cannot activate transcription when only one TRE is
available.
In contrast to the interaction between MEF-2a and T3Rs in
the absence of T3, which is not T3R isoform
specific, T3 can further transactivate SERCA 2 gene
expression in the presence of MEF-2a only in the presence of
T3Rß1. These results demonstrate a T3R
isoform-specific interaction with the muscle-specific transcription
factor MEF-2a. The simultaneous occurrence of the products of
T3R1 and the T3Rß gene, primarily
T3Rß1, but also T3Rß2, in cardiac myocytes
could serve different purposes. The occurrence of the two different
T3R genes coding for functional T3Rs could
present an evolutionary safety feature, assuring that if only one
T3R gene is inactivated, the second gene could continue
with T3R function. Such an explanation would not fit the
observation that other functionally important genes, such as the SERCA
2 gene, occur only as one isoform. Our results showing the specific
interaction of MEF-2a with T3Rß1 in the presence of
T3 would imply that the different T3R isoforms
can interact with cell type-specific factors and exert complex
regulatory influences on the expression of specific genes in different
cells. MEF-2a contributes to determining the lineage of myocytic cells,
and this myocytic transcription factor persists in fully differentiated
myocytes (15). Our results (data not shown) indicate that an abundant
amount of MEF-2 is present in cardiac myocytes, and addition of
exogenous MEF-2a in these cells by transfection experiments leads to
squelching of transcription factors. Related to the
T3Rß1-specific transactivation induced by T3
in the presence of MEF-2a, it is of interest to note that the
N-terminuses of T3R and -ß isoforms, in contrast to
the DNA and dimerization domains, exhibit very low amino acid sequence
homology. Therefore, it is quite possible that this domain may be
critical in mediating T3R-specific isoform transactivation
activities. Considering this information, we anticipated that the
T3Rß1 N-terminus could play a role in the
ligand-dependent T3Rß1/MEF-2a isoform-specific
interaction. This prediction is confirmed by the data presented in Fig. 1b. The mutant NMT3Rß1, which expresses an
N-terminus-deleted T3Rß1, is not able to mimic the
T3-dependent T3Rß1-specific interaction with
MEF-2a. It is possible that the T3Rß/MEF-2a interaction
(in a DNA MEF-2-binding site-dependent or independent manner) promotes
the disassociation between T3Rs and corepressors (38) or
basal transcription complex factors, such as TFIIB (39), leading to
derepression of transcription. The presence of T3 may
trigger the association of coactivators with the N-terminus of
T3Rß1, leading to further increases in gene
transcription. Recent results suggest that T3Rs are able to
physically interact with potential coregulators (40). Further attention
has been directed to the T3Rs N-terminus because it was
found that this region has a transactivation activity termed AF1 (11).
Based on the fact that this region, in the T3Rs, presents
significant differences in amino acid sequence, it might be possible
that the AF1 region, in contrast to the AF2 region that possesses a
much more conserved sequence, is flexible enough to allow specific
interactions with different nuclear factors.
The specificity of the interaction between T3R and MEF-2a is indicated by the finding that other transcription factors which interact with the SERCA 2 regulatory region cannot substitute for MEF-2a. The cardiac myocyte-specific HF-1b, which binds to A/T-rich elements in the myosin light chain 2 promoter with a nucleotide sequence similar to MEF-2 consensus sites, does not interact with T3Rs, but increases SERCA 2 transcription by itself. In addition, cotransfection of the CREB transcription factor and a constitutively active PKA increases SERCA 2 transcription, but no specific interaction occurs with MEF-2a. The same holds true for the Egr-1 transcription factor. This factor leads to a 10-fold increase in SERCA 2 transcription, which is not modified by the presence of MEF-2a.
Considering that MEF-2a is not only important for myogenesis, but is also implicated in the maintenance and regulation of muscle-specific genes in fully differentiated cells, the interaction of T3R/MEF-2a provides further insight into how unliganded and liganded T3R isoforms, by binding to relatively simple cis elements such as TREs, can provide complex regulation of transcription in a tissue-specific manner.
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Footnotes |
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1 This work was supported by NIH Grant HL-25022. 
2 Recipient of a fellowship from the Brazilian Conselho Nacional de
Pesquisa.
Received May 21, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene expression in
cardiac myocytes. J Biol Chem 266:8638–8646- and ß-thyroid hormone receptor mRNAs,
including the ß2-subtype, in the developing mammalian nervous system.
J Neurosci 12:2288–2302[Abstract]
1,
ß1, but not ß2 contains a strong thyroid hormone-dependent
transactivation function. Biochemistry 92:5600–5604
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