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(Received for publication, October 13, 1995; and in revised form, December
22, 1995) From the
An upstream inverted repeat (IR) element mediates
transcriptional activation of the interferon response factor-1 gene (IRF-1) by interferon (IFN)- Many cytokine and growth factor signaling pathways utilize
proteins of the JAK ( IFN- Transcription of the IRF-1 gene is inducible by both
IFN- In this report, we demonstrate the formation of a novel
IFN-
Figure 1:
STAT1-STAT2 heterodimers in extracts of
IFN-
Figure 2:
Alteration of the relative amounts of
STAT1-STAT2 heterodimers and STAT1 homodimers in U6A cells. The details
are the same as in Fig. 1A, except that extracts from
transfected U6A cells overexpressing STAT2 or a STAT2-STAT1 chimera (N2; see ``Materials and Methods'') were
used.
Figure 3:
STAT1-STAT2 heterodimers and STAT1
homodimers both activate transcription of the IRF-1 gene in
response to IFN-
It has been
proposed that the STAT1 homodimer also functions as a transcriptional
activator of this gene in IFN- Although
both STAT1-STAT2 heterodimers and STAT1 homodimers can activate IRF-1, it is likely that the heterodimer is more potent. Upon
IFN-
Figure 4:
STAT2 proteins with C-terminal truncations
form heterodimers with STAT1. Extracts were prepared from U6A cells
transfected with wild-type STAT2 or STAT2 C-terminal deletion
constructs, using clones with similar levels of expression. The end
points of the deletions are indicated. The sizes of the STAT1-STAT2
heterodimers (arrows) decreased as the length of the deletions
increased.
Figure 5:
Complementation of IFN-
Figure 6:
Alteration of the ratio of ISGF3 to
STAT1-STAT2 heterodimers by p48. A, EMSA was performed using
extracts of either U2A or p48-complemented U2A cells,
untreated(-) or treated with IFN-
We performed EMSA with various GAS elements (1) and
an extract of U6A/STAT2 cells; only the IR and Fc STAT1-STAT2 heterodimers form in U2A
cells in the absence of p48. It is likely that p48 binds to preformed
heterodimers to form ISGF3, so that the level of p48 can influence the
steady-state amount of heterodimer. The expression of p48 is usually
low in most cell types but can be induced by IFN- We manipulated the amounts of
STAT1-STAT2 heterodimers and STAT1 homodimers in transfected U6A cells
to reveal that both can function to stimulate transcription of the IRF-1 gene in response to IFN- We showed by deletion analysis that the
acidic domain of STAT2 is important for the transcriptional activation
of the IRF-1 gene. The same region is also important for
transcriptional activation of ISRE-containing genes(29) . It is
possible that the acidic domain of STAT2 may interact with the same
basic transcription factor(s) at the start sites of these genes. We
detected truncated heterodimers and STAT1 homodimers in U6A cells
transfected with a series of STAT2 proteins carrying C-terminal
deletions and found that decreased IRF-1 induction correlated
with shortening of the STAT2 acidic domain. The STAT1 homodimers formed
in these cells are insufficient to induce IRF-1 transcription,
probably because they fail to compete effectively with the defective
heterodimers. Although a STAT1-STAT3 heterodimer (complex B) was
detected using the IR element probe, this species is unlikely to be
important for IFN- In summary, we have demonstrated
an alternative transcriptional activation pathway mediated by a novel
transcription factor that is likely to be a STAT1-STAT2 heterodimer.
The heterodimer binds to the IR element of the IRF-1 gene and
the GAS element of the Fc
Volume 271,
Number 10,
Issue of March 8, 1996 pp. 5790-5794
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
(*)
and IFN-. IFN-
and
IFN- fail to induce IRF-1 in cells that lack signal
transducer and activator of transcription 1 (STAT1), and STAT1
homodimers bind to IR elements in extracts of IFN-
-treated cells.
We now report that STAT2 also plays an important role in the
IFN--mediated transcriptional activation of the IRF-1 gene. A new factor, most likely a STAT1-STAT2 heterodimer, was
detected with an IR probe in extracts of IFN--treated cells. STAT1
and STAT2 are already known to combine with p48, a DNA-binding protein,
to form IFN-stimulated gene factor 3 (ISGF3), which binds to
IFN-stimulated response elements (ISREs) distinct from the IR of the IRF-1 gene. In extracts of U2A cells, which lack p48,
STAT1-STAT2 heterodimers were still formed, indicating that they do not
contain p48. We manipulated the intracellular levels of STAT1-STAT2
heterodimers and STAT1 homodimers to examine their roles in the
induction of IRF-1 by IFN-. Although both dimers can
induce IRF-1 transcription, the heterodimers are more potent
and thus may be the major activators in vivo. Deletion
analysis reveals that the C-terminal domain of STAT2 is important for
transcriptional activation mediated by both STAT1-STAT2 heterodimers
and ISGF3.
)and STAT families (1, 2, 3) . The IFN- pathway involves
activation of TYK2, JAK1, STAT1, and STAT2. The two STAT proteins are
phosphorylated on conserved tyrosine residues by the JAK family kinases
when IFN- binds to the receptor complex(3) . Activated
STAT1 and STAT2 associate with the DNA-binding protein p48 to form the
transcription factor ISGF3, which recognizes an interferon-stimulated
response element (ISRE, consensus: AGTTTCNNTTTCN(C/T)) (2) present in many promoters activated by IFN- (for
examples, see (4, 5, 6) ). All three proteins
of ISGF3 make contact with DNA(7) . triggers the
tyrosine phosphorylation of STAT1, but not STAT2 (8) .
Activated STAT1 forms homodimers, known as GAF(9) . In
IFN-
signaling, a complex containing STAT1, biochemically similar
to GAF, has been reported(10) . The GAS DNA sequences
(consensus: TTNCNNNAA) recognized by GAF serve as binding sites for
various cytokine- or growth factor-activated STAT proteins, including
STAT3 homodimers(11, 12) , STAT1-STAT3
heterodimers(11, 12) , STAT4(13) ,
STAT5(14, 15, 16) , and STAT6(17) . and IFN-. A 16-kb 5`-flanking region that mediates a
response to either IFN-
or - does not contain an ISRE, and
the induction of IRF-1 by IFN-
is independent of the p48
subunit of ISGF3 (18, 19, 20) .
Transcriptional activation of this IRF-1 promoter segment by
IFNs requires a palindromic GAS element, the IR element, which lies
about 110 bases upstream of the transcription start site. IFN-inducible
transcription factors containing STAT1 bind to the IR element in
vitro.-inducible DNA-binding factor consisting of STAT1 and STAT2.
Although this factor does not include p48, the level of p48 protein
does affect the balance between the novel factor and ISGF3. We propose
that transcriptional activation of the IRF-1 gene involves
interaction of the IR element with either a STAT1-STAT2 heterodimer or
a STAT1 homodimer.
Cells and IFNs
2fTGH and mutant cell lines
derived from it have been described elsewhere(21) . Human
recombinant IFN- (5 
10
IU/ml) was obtained
from Hoffmann LaRoche. IFN- (8.3
10 IU/mg) was
from Genentech.RNase Protection Assay
Total RNA was prepared from
IFN-treated cells and protection experiments were performed as
described by Sambrook et al.(22) . The probes used
protect 175 bases of IRF-1 or 130 bases of and -actin
mRNAs (23) .
EMSA
The oligonucleotides used were: IR element,
5`-GTGATTTCCCCGAAATGACG-3`; Fc GAS, 5`-GTATTTCCCAGAAAAGGAAC-3`.
Briefly, complementary oligonucleotides, end-labeled with
polynucleotide kinase (Boeringer Mannheim) and
[
-
P]ATP, were annealed by slow cooling.
Approximately 20,000 cpm of probe were used per assay. Cytoplasmic
extracts were prepared, and assays were carried out as described
previously(24, 25) . Briefly, the binding reaction was
carried out in a total volume of 12.5-20 µl in 20 mM Hepes buffer, pH 7.0, 10 mM KCl, 0.1% Nonidet P-40, 0.5
mM dithiothreitol, 0.25 mM phenylmethanesulfonyl
fluoride, and 10% glycerol at room temperature for 20 min. For
supershift experiments, the extract was incubated with 1 µl of
antibody for 15 min at 4 °C before adding the probe. The antibodies
used were against STAT1(26) , STAT2(27) ,
STAT3(12) , p48(28) , and WAF-1 (Transduction
Laboratories). Control rabbit preimmune serum was from Sigma.
Transfections
Wild-type and C-terminal deletion
constructs of STAT2 (29) were transfected into U6A cells by the
calcium phosphate method(30) . STAT2 proteins were analyzed by
Western blotting and clones expressing similar levels were used. The N2
chimera was constructed by the polymerase chain reaction SOEing
technique(31) , replacing the N-terminal region of STAT1 (amino
acids 1-305) with the corresponding region of STAT2 (amino acids
1-315)(27) .
Detection of a GAS-binding Transcription Factor
Containing STAT1 and STAT2
Complex formation with various GAS
element probes was examined by EMSA using cytoplasmic extracts of 2fTGH
cells. At least three IFN--inducible DNA-binding factors were
detected by using an IR element as probe (Fig. 1A, lane 2). We designate these complexes A, B, and C, from the
slowest mobility to the fastest, respectively. The intensity of complex
C was at least five times higher than that of complex A, and the
intensity of complex B was weakest. Similar results were obtained using
an Fc GAS probe. (
)We used antibodies against STAT1,
STAT2, and STAT3 to analyze the components present in these complexes.
Complex C, which migrated similarly to the IFN--induced GAF (Fig. 1A, lane 3), was supershifted only by an
antibody against STAT1 (Fig. 1B, lane 2).
Complex B was supershifted by antibodies against STAT1 or STAT3 (Fig. 1B, lanes 2 and 4). Complex A
was supershifted by antibodies against STAT1 or STAT2 (Fig. 1B, lanes 2 and 3). A control
antibody against WAF-1 did not supershift any of these complexes (Fig. 1B, lane 5). (The control antibody did
generate nonspecific protein-DNA complexes near the top of the gel.)
The composition of complexes A, B, and C was analyzed further by
comparing 2fTGH and mutant cell extracts. No complex was detected with
an extract of U3A cells, which lack STAT1
, and complex A
was not detected in IFN--treated U6A cells, which lack STAT2 (Fig. 1A, lane 5). Complex C was barely
detectable in IFN--treated U6A cells (Fig. 1A, lane 5), probably due to the weak activation of STAT1 in the
absence of STAT2(23) . Thus, it is likely that complex C
contains STAT1 homodimers, complex B contains STAT3-STAT1 heterodimers,
and complex A contains STAT1-STAT2 heterodimers. To establish that
complex A does not contain p48, we performed an EMSA with an extract of
IFN--treated U2A cells, which lack p48 (Fig. 1C).
Complex A was still detectable in these cells, showing that STAT1-STAT2
heterodimers can bind to DNA in the absence of p48. The bands formed
with the U2A extract were less intense than those formed with 2fTGH
extracts (Fig. 1B) for an unknown reason, possibly
clonal variation.
-treated cells. A, EMSA was performed using cell
extracts prepared from 2fTGH or U6A cells, untreated(-) or
treated with IFN- () or IFN- (
) for 15 min. An IR
probe was used. Complexes A, B, and C are indicated by arrows.
B, an extract from IFN-
-treated 2fTGH cells was assayed with
an IR probe. Antibodies against STAT1 (S1), STAT2 (S2), STAT3 (S3), or Waf-1 (W) were included
in the binding reactions as indicated. C, same as B,
except that extracts of U2A cells were
used.
STAT1-STAT2 Heterodimers and STAT1 homodimers Are Both
Transcriptional Activators of the IRF-1 Gene
The IR element of
the IRF-1 promoter binds IFN--inducible factors
containing STAT1 and is important for the transcriptional activation of IRF-1 in response to
IFNs(18, 19, 20) . Previously, we showed that
IFN- induction of IRF-1 in U6A cells (lacking STAT2) was
greatly reduced(23) . We have now manipulated the levels of the
heterodimers and homodimers, to evaluate their roles in the activation
of IRF-1 transcription. To evaluate the heterodimers, we used
a U6A clone, transfected with a STAT2 expression construct, that
expresses about 10 times more STAT2 protein than 2fTGH cells. Parental 2fTGH cells have much less heterodimer than homodimer (Fig. 1A, lane 2). The high level of STAT2 in
the transfected U6A clone greatly increases the formation of
heterodimers and decreases the formation of homodimers in response to
IFN- (Fig. 2, lane 2). The ratio of heterodimers
to homodimers in this clone changes to 5:1 compared to a ratio of about
1:5 in parental 2fTGH cells (Fig. 1A, lane 2),
a 25-fold increase. IFN--induced IRF-1 expression was
restored in this clone (Fig. 3, U6A/STAT2). The results
suggest that the STAT1-STAT2 heterodimer can function as a
transcriptional activator of the IRF-1 gene.
. A, total RNAs, prepared from 2fTGH,
U3A, U6A, U6A/STAT2, and U6A/N2 cells, were analyzed by RNase
protection, using probes for IRF-1 and -actin. The cells
were untreated or treated with IFN-
for 1 or 4 h. The protected
fragments are indicated by arrows. A shorter exposure is also
shown for the -actin fragment. B, quantitation of the
experiment. The intensities of the bands were measured by use of a
PhosphoImager (Molecular Dynamics). The signals were normalized to
-actin.
-treated cells(20) . To
evaluate the role of the homodimer in the absence of the heterodimer,
we expressed in U6A cells a chimeric protein, designated N2, in which
the N-terminal 305 amino acids of STAT1 are replaced by the N-terminal
315 amino acids of STAT2. We observed only STAT1 homodimers in
IFN--treated U6A/N2 extracts (Fig. 2, lane 5). In
response to IFN-, IRF-1 induction was restored in U6A/N2
cells (Fig. 3), suggesting that STAT1 homodimers are also
transcriptional activators of the IRF-1 gene. The N2 protein
and endogenous STAT1 were both phosphorylated in response to IFN-
in U6A/N2 cells. However, we did not detect
co-precipitation of N2 with STAT1 in these cells, suggesting that N2 dimerizes poorly with STAT1. Furthermore,
complex C in U6A/N2 extracts is not likely to contain N2/STAT1
heterodimers or N2/STAT1 heterodimers because an amount of an antibody
against N-terminal STAT2 that could supershift all of complex A in
2fTGH cells (Fig. 1B, lane 3) showed only
minimal effect on complex C in U6A/N2 cells. treatment, the level of homodimers in U6A/N2 cells was about
10-fold higher than the level of heterodimers in U6A/STAT2 cells (Fig. 2; compare complex C in lane 5 to complex A in lane 2). However, induction of IRF-1 gene expression
was stronger in U6A/STAT2 cells than in U6A/N2 cells 4 h after
IFN- treatment (Fig. 3, A and B; compare
U6A/STAT2 to U6A/N2). Although there are more STAT1 homodimers than
STAT1-STAT2 heterodimers in IFN--treated 2fTGH cells (Fig. 1A, lane 2), the heterodimers may still
contribute to the activation of IRF-1 gene expression, since
they are more potent.The Acidic Domain at the C Terminus of STAT2 Is Required
for IFN-
The critical role of
STAT1-STAT2 heterodimers in IFN--induced IRF-1 Transcription-induced IRF-1 expression
is supported by studies with a series of C-terminal STAT2 deletion
mutants. The STAT2 C terminus contains a domain rich in acidic amino
acids, believed to be important to transcriptional
activation(27) . Recently, we expressed a series of C-terminal
STAT2 deletion mutants in U6A cells and showed that the acidic domain
is important for ISGF3-mediated transcriptional activation in response
to IFN-(29) . A U6A clone expressing full-length STAT2
(851 amino acids) was compared to clones expressing similar levels of
STAT2 deletions missing 20 (
831 construct), 39 (812
construct), or 51 (800 construct) C-terminal amino acids. In all
of these clones, the IFN--mediated tyrosine phosphorylation of
STAT1 was restored to normal levels (29) and heterodimers of
STAT1 and the truncated STAT2 proteins (Fig. 4, complex
A) and STAT1 homodimers (Fig. 4, complex C) were
formed. Interestingly, IRF-1 gene induction could not be
restored by STAT2 mutants with deletion of 51 amino acids (Fig. 5, 800) or more. At least three factors contribute to
this result. First, the STAT1-800-STAT2 heterodimers are likely to
be inherently defective in transcriptional activation. Second, the
small amounts of STAT1 homodimers formed in these clones will activate IRF-1 transcription only inefficiently. Third, the inactive
heterodimers are likely to compete with the homodimers for IR elements.
In summary, the segment between amino acids 851 and 800 is important
for IRF-1 gene transcription mediated by the STAT1-STAT2
heterodimers and also for the transcriptional activity of STAT1-STAT2
heterodimers bound to p48 (ISGF3)(29) .
-induced IRF-1 expression in U6A cells by full-length STAT2 or STAT2
proteins with C-terminal truncations. The amino acid positions at the
C-terminal ends of the deletions are indicated. Total RNAs were
analyzed by RNase protection, using probes for IRF-1 and -actin.
The cells were untreated(-) or treated with IFN-
for 4 h
(). The positions of the protected fragments and undigested probes
are indicated by arrows. A shorter exposure is also shown for
the -actin fragment.
Inhibition of Complex A Formation by
p48
Overexpression of p48 should reduce the amount of
STAT1-STAT2 heterodimers by promoting ISGF3 formation. In U2A cells
(lacking p48), ISGF3 was not formed in response to IFN- (Fig. 6A, lane 4), but the heterodimer was
detected with the IR element probe (Fig. 6B, lane
4). When p48 was overexpressed in U2A cells, the ISGF3 complex was
formed (Fig. 6A, lane 2), but the heterodimer
(complex A) was not detected, even when twice the amount of extract was
used (Fig. 6B, lane 2), suggesting that the
level of STAT1-STAT2 heterodimers is affected by the level of p48.
Formation of complex C (STAT1 homodimers) was not affected in
p48-transfected U2A cells.
for 15 min. An ISRE probe
from the 9-27 gene was used (GGAAATAGAAACT)(5) . The
position of ISGF3 is indicated by arrows. We see two bands,
corresponding to the 91- and 84-kDa forms of STAT1. B, the
same extracts were assayed with an IR probe (see ``Materials and
Methods''). To show critically that complex A was not present in
the IFN--treated U2A/p48 cells, the amount of extract was doubled
in that lane. Complexes A and C are indicated by arrows.
GAS elements
were found to bind STAT1-STAT2 heterodimers, suggesting that the
heterodimers probably prefer GAS elements with the core sequence
TTCCC(A/C)GAA. We did not identify a GAS element specific for
heterodimers since STAT1 homodimers were detected with the same probes.
It will be interesting to determine the optimal GAS sequence for
binding heterodimers by use of the polymerase chain
reaction(32) . However, the optimal sequence for STAT1-STAT2
heterodimers may be no more specific than the optimal sequence for
STAT1-STAT3 heterodimers, which also binds to STAT1 homodimers with
high affinity(32) .
. Thus, the
heterodimer may be directed either to form ISGF3 or to bind to a
selected set of GAS elements depending on the availability of p48,
which thus may modulate the response to IFN-
in an
IFN--dependent manner.
. However, a small amount
of heterodimer is sufficient to promote a high level of IRF-1 induction, revealing that this novel factor is a potent
transcriptional activator. The STAT1 homodimers induced by IFN-
activate IRF-1 transcription less strongly. Our results
suggest that, depending on the level of p48, STAT1-STAT2 heterodimers
can play a major role in activating IRF-1 transcription in
response to IFN-.-mediated IRF-1 gene expression because
the amount of complex B is very low. The role of STAT3 in the IFN-
signaling pathway remains unclear. gene and is a potent transcriptional
activator of the IRF-1 gene. Since the IRF-1 protein has been
found to be a tumor suppressor (33) and a mediator of
apoptosis(34) , the STAT1-STAT2 heterodimer may play an
important role in the antiproliferative response mediated by type I
IFNs.
), high affinity
immunoglobulin G chain receptor gene; GAF,
-activated factor; GAS,
-activated sequence; IFN, interferon; IR, inverted repeat; IRF-1,
interferon response factor-1; ISGF3, interferon-stimulated gene factor
3; ISRE, interferon-stimulated response element; p48, 48-kDa DNA
binding component of ISGF3; SH2, Src-homology domain 2; STAT, signal
transducer and activator of transcription; WAF-1, wild-type
p53-activated factor 1.
)
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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 K. M. McAveney, M. L. Book, P. Ling, J. Chebath, and L.-y. Yu-Lee Association of 2',5'-Oligoadenylate Synthetase with the Prolactin (PRL) Receptor: Alteration in PRL-Inducible Stat1 (Signal Transducer and Activator of Transcription 1) Signaling to the IRF-1 (Interferon-Regulatory Factor 1) Promoter Mol. Endocrinol., February 1, 2000; 14(2): 295 - 306. [Abstract] [Full Text]
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M. Paulson, S. Pisharody, L. Pan, S. Guadagno, A. L. Mui, and D. E. Levy Stat Protein Transactivation Domains Recruit p300/CBP through Widely Divergent Sequences J. Biol. Chem., September 3, 1999; 274(36): 25343 - 25349. [Abstract] [Full Text] [PDF]
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I. Dumler, A. Kopmann, K. Wagner, O. A. Mayboroda, U. Jerke, R. Dietz, H. Haller, and D. C. Gulba Urokinase Induces Activation and Formation of Stat4 and Stat1-Stat2 Complexes in Human Vascular Smooth Muscle Cells J. Biol. Chem., August 20, 1999; 274(34): 24059 - 24065. [Abstract] [Full Text] [PDF]
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S. Mukhopadhyay, A. George, V. Bal, B. Ravindran, and S. Rath Bruton's Tyrosine Kinase Deficiency in Macrophages Inhibits Nitric Oxide Generation Leading to Enhancement of IL-12 Induction J. Immunol., August 15, 1999; 163(4): 1786 - 1792. [Abstract] [Full Text] [PDF]
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E. Le Roy, A. Mühlethaler-Mottet, C. Davrinche, B. Mach, and J.-L. Davignon Escape of Human Cytomegalovirus from HLA-DR-Restricted CD4+ T-Cell Response Is Mediated by Repression of Gamma Interferon-Induced Class II Transactivator Expression J. Virol., August 1, 1999; 73(8): 6582 - 6589. [Abstract] [Full Text]
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D. M. Miller, Y. Zhang, B. M. Rahill, W. J. Waldman, and D. D. Sedmak Human Cytomegalovirus Inhibits IFN-{alpha}-Stimulated Antiviral and Immunoregulatory Responses by Blocking Multiple Levels of IFN-{alpha} Signal Transduction J. Immunol., May 15, 1999; 162(10): 6107 - 6113. [Abstract] [Full Text] [PDF]
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N. E. S. Sibinga, H. Wang, M. A. Perrella, W. O. Endege, C. Patterson, M. Yoshizumi, E. Haber, and M.-E. Lee Interferon-{gamma}-mediated Inhibition of Cyclin A Gene Transcription Is Independent of Individual cis-Acting Elements in the Cyclin A Promoter J. Biol. Chem., April 23, 1999; 274(17): 12139 - 12146. [Abstract] [Full Text] [PDF]
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M. R. S. Rani, C. Gauzzi, S. Pellegrini, E. N. Fish, T. Wei, and R. M. Ransohoff Induction of beta -R1/I-TAC by Interferon-beta Requires Catalytically Active TYK2 J. Biol. Chem., January 22, 1999; 274(4): 1891 - 1897. [Abstract] [Full Text] [PDF]
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 W. Min, J. S. Pober, and D. R. Johnson Interferon Induction of TAP1 : The Phosphatase SHP-1 Regulates Crossover Between the IFN-{alpha}/ß and the IFN-{gamma} Signal-Transduction Pathways Circ. Res., October 19, 1998; 83(8): 815 - 823. [Abstract] [Full Text] [PDF]
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ABSTRACT
