Circulation Research. 1997;81:457-461
(Circulation Research. 1997;81:457-461.)
© 1997 American Heart Association, Inc.
Inducible Expression of Egr-1Dependent Genes
A Paradigm of Transcriptional Activation in Vascular Endothelium
Levon M. Khachigian,
,
Tucker Collins
From The Centre for Thrombosis and Vascular Research (L.M.K.), School of
Pathology, The University of New South Wales, Sydney, Australia, and the
Vascular Research Division (T.C.), Brigham and Women's Hospital and
Harvard Medical School, Boston, Mass.
Correspondence to Levon M. Khachigian, PhD, The Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales, Sydney NSW 2052, Australia. E-mail L.Khachigian{at}unsw.edu.au
Key Words: early growth response factor-1 platelet-derived growth factor transcription
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Introduction
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Throughout
the vascular network, endothelium forms the continuous
cellular
interface between the circulating blood elements and the
surrounding
tissues. These cells provide a nonthrombogenic surface and
a
permeability barrier capable of modulating blood flow and vascular
reactivity.
As such, the integrity of the endothelium
is a fundamental requirement
for the maintenance of normal
homeostasis. Injury to this lining
and the subsequent inflammatory
response are among the earliest
cellular events in the pathogenesis of
atherosclerosis.
1 This
can result in
dramatic phenotypic changes that render otherwise
quiescent
endothelium adhesive and prothrombotic. Lesions of
atherosclerosis
and postangioplasty restenosis
may develop under the influence
of molecules inducibly expressed or
simply released by activated
or injured
endothelium. Several lines of evidence over the last
decade,
based on ligand and receptor localization, overexpression, and
infusion
studies, have correlated PDGF with the development of vascular
occlusive
lesions. PDGF appears to play a regulatory role in the
migratory,
rather than proliferative, events associated with the
response
to arterial injury. PDGF expression is quite low
in the quiescent
vessel wall, but levels of the growth factor increase
substantially
after injury. This Mini Review will focus on the
transcriptional
mechanisms underlying inducible PDGF expression in
vascular
endothelium and smooth muscle cells, with
particular emphasis
on the role played by the early growth response
gene product,
Egr-1.
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Sp1 Mediates Basal PDGF Gene Expression
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The vessel wall responds to a changing local environment by
modulating
the expression of specific sets of genes. Transcriptional
activation
in response to these signals involves the regulated assembly
of
multiprotein complexes on promoters. The promoter regions of
the
PDGF-A and PDGF-B genes have been characterized, and some
of the
regulatory sequences and transcriptional activators have
been
defined. In endothelial cells, 5' deletion
analysis of both
promoters has determined that the minimal
promoters consist
of

100 bp.
2 3 The zinc-finger
transcription factor, Sp1, was
the first endogenous nuclear
factor found to interact with the
PDGF-A promoter
2 and
PDGF-B promoter.
3 Sp1 binds to consensus
elements in the
proximal PDGF-A promoter
2 as well as to the
5'-CCACCC-3'
motif in the proximal PDGF-B promoter.
3 4 Cotransfection
and
mutational studies revealed that the ability of Sp1 to bind
is
critical for basal expression driven by the PDGF-A
2 and
PDGF-B
3 promoters in cultured cells, consistent
with "housekeeping"
roles for this factor reported
elsewhere.
5 In vivo footprinting
indicates that the Sp1
site in the PDGF-B promoter is occupied
by nuclear factor(s) in intact
cells.
6 Moreover, the proximal
region of the PDGF-A
promoter spanning the Sp1 site is sensitive
to cleavage by S1
nuclease,
7 consistent with the possibility
that
this region of the PDGF-A gene contains functional promoter
elements.
Sp1 and other factors may activate PDGF transcription
and
account for the low levels of expression observed in the
resting vessel
wall. Alternatively, they may serve as architectural
proteins
maintaining chromatin structure in such a way that
enables these genes
to be readily activated by inducible transcription
factors.
Whereas these findings implicate a regulatory role
for the region
immediately upstream from the TATA box of both
genes, transcription
factors associating with other elements
in the gene may interact with
transactivators in the core promoter
and/or the basal
complex to generate the authentic pattern of
PDGF gene expression.
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Interplay of Egr-1 and Sp1 Over Promoter Elements
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We used PMA as a model agonist to explore the regulatory processes
underlying
the inducible expression of PDGF-A and PDGF-B in
endothelial
cells. PMA-response elements in both
promoters were localized
to the proximal Sp1 binding sites by 5'
deletion and transient
transfection analysis.
2 3
However, electrophoretic mobility
shift assays and Northern blot
analysis determined that Sp1
levels were unchanged in cells
exposed to PMA.
2 The Sp1 sites
in the PDGF-A promoter
overlap with a number of consensus elements
for the structurally
related transcription factor, Egr-1,
8 also known as TIS8,
krox-24, and NGFI-A. Egr-1 transcript and
protein levels are low or
undetectable in quiescent endothelial
cells but are
dramatically increased upon exposure to PMA.
2 We showed
that both recombinant and endogenous nuclear Egr-1
can bind
to the PDGF-A PMA-response element.
2 Transfection
analysis
indicates that this interaction is crucial for
PMA-inducible
PDGF-A promoterdependent expression in
endothelial cells.
2 Similar strategies
later revealed that Egr-1 binds to a cryptic
element overlapping the
Sp1 site in the PDGF-B promoter in cells
exposed to
PMA.
9
Since Sp1 occupies both PDGF promoters in resting cells, we
hypothesized that inducible PDGF expression mediated by Egr-1 involves
displacement of prebound Sp1 from their overlapping binding sites
(Figure
). Using recombinant proteins, we
found that Egr-1 was capable of displacing prebound Sp1 from both PDGF
promoters.2 9 Displacement was also observed in nuclear
extracts of cells exposed to PMA.2 9 10 Interplay of
regulatory transcription factors may be a common theme in inducible
gene expression. Displacement has been suggested to occur in
endothelial cells exposed to the proinflammatory
cytokine TNF-
. TNF-
stimulates the nuclear translocation
of nuclear factor-
B p50-p65, which activates transcription
after p50-p50 homodimers are displaced from common binding sites. p50
is constitutively expressed and cannot activate transcription
by itself because it does not contain a transcriptional activation
domain. Using the Egr-1/Sp1 paradigm, we explored the possibility that
Egr-1 modulates PDGF-A expression in
pathophysiologically-relevant settings.

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Figure 1. Model of the cascade of molecular events underlying the
inducible expression of Egr-1dependent genes in vascular
endothelial cells. Multiple extracellular stimuli
activate phosphorylation-dependent signaling
pathways, which converge at the Egr-1 promoter (see text). Upon
synthesis, Egr-1 translocates to the nucleus and activates gene
expression after displacing Sp1.
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Egr-1 Is Activated by Multiple
(Patho)physiological Stimuli and Plays a Positive
Regulatory Role in the Inducible Expression of Several Endothelial
Genes
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PDGF-A and PDGF-B are expressed at low or undetectable levels
in
the unmanipulated rat artery wall. Upon denudation of aortic
endothelium,
however, these genes are inducibly
expressed at the wound edge.
11 On the basis of our in
vitro observations with PMA, we explored
the possibility that Egr-1
might also be involved in the inducible
expression of these genes in
the injured vessel wall. In situ
hybridization with en face
preparations determined that the
inducible expression of PDGF-A and
PDGF-B is preceded by a dramatic
and transient increase in Egr-1
transcripts at the same location.
9 Nuclear runoff
experiments revealed that Egr-1 is activated
at the level of
transcription in endothelium injured in
vitro.
9 Egr-1 induced by injury binds to the proximal
PDGF-A and PDGF-B
promoters and can displace Sp1 from both
genes.
9 This provided
the first direct link between a
transcription factor and a target
gene in the context of vascular
injury. Interestingly, several
other genes, whose products
influence chemotactic, proliferative,
and thrombogenic events
associated with vascular occlusive lesions,
are targets of Egr-1. These
include tissue factor, TGF-ß
1,
and u-PA
(Table

). These genes, like both chains of
PDGF, are
expressed at the wound edge only after the transient
appearance
of Egr-1.
9 In binding studies with recombinant
proteins, we
found that Sp1 could be displaced from the proximal
promoters
of each of these genes by Egr-1.
9 Accordingly,
competitive
interactions between Egr-1 and Sp1 may be a common theme in
the
inducible expression of multiple
pathophysiologically relevant
genes in response
to injury.
The first smooth muscle cells to migrate from the media to the intima,
a week or so after endothelial denudation in the rat
artery, do so at the wound edge.12 Since "gentle"
injury does not physically traumatize underlying smooth
muscle,13 factors released by damaged
endothelium may contribute to this paracrine
chemotactic response. FGF-2 lacks a classic signal peptide for
exocytotic secretion. Consequently, it is found preformed in
endothelial and smooth muscle cells both in culture and
in the artery wall. We hypothesized that inducible Egr-1 and PDGF
expression following endothelial injury may be due to
the release and local action of FGF-2. Exposure of
endothelial cells to FGF-2 induced the expression and
nuclear accumulation of Egr-1. Egr-1 bound to the proximal PDGF-A
promoter before the inducible expression and secretion of PDGF-AA.
Preincubation of endothelial monolayers with
neutralizing antibodies to FGF-2 profoundly inhibited the induction of
Egr-1 and its interaction with the PDGF-A promoter. Thus,
endogenous FGF-2 contributes to the activation of Egr-1
upon endothelial injury (L.M. Khachigian, unpublished
data, 1997). PDGF synthesized and secreted by
endothelial cells may, in turn, induce further growth
factor expression in smooth muscle cells via Egr-1/Sp1 interplay in a
paracrine manner.10
The nonrandom spatial distribution of early atherosclerotic lesions in
humans and animal models and the positive correlation of these lesions
with disturbed blood flow patterns14 has suggested that
local hemodynamic factors could influence the normal
structure and function of endothelium in the vessel
wall.15 Alterations in blood flow and shear stress in
surgically manipulated baboon arteries result in elevated PDGF-A mRNA
expression and protein levels in the
endothelium.16 In collaborative studies
with Dr Michael Gimbrone, Jr, and colleagues (Dewey et
al17 ), we used a well-characterized in vitro mechanical
model to apply physiological levels of laminar
shear stress (10 dyne/cm2) to endothelial
monolayers and found that PDGF-A mRNA is also inducibly expressed in
this setting.18 Nuclear runoff studies determined that
this increase is mediated, at least in part, at the transcriptional
level.18 Deletion analysis of the PDGF-A promoter
defined the Sp1/Egr-1 binding site as an SSRE. Although Egr-1
transcript levels increased in endothelial cells
exposed to shear stress, Sp1 levels were not significantly altered.
Egr-1 protein translocates to the nucleus minutes after the application
of shear, where it binds to the PDGF-A SSRE after displacing Sp1
(Figure
). This interaction is crucial for shear-inducible PDGF-A
promoterdependent expression.18 Taken together, these
findings demonstrate that Egr-1 is activated in
endothelial cells exposed multiple stimuli and may in
turn be a pluripotent inducer of other genes. Recent evidence suggests
that shear-inducible tissue factor expression also involves the
interplay of Egr-1 and Sp1 in the proximal promoter,19
although Sp1 hyperphosphorylation has also been
implicated in the induction of this gene.20
 |
Authentic Targets for Egr-1: Lessons From Mice With a Targeted
Mutation in Egr-1
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Establishing authentic biological roles for Egr-1 is a key
unresolved
issue. One approach to this challenge is a loss-of-function
strategy
in which mice are produced with a targeted mutation in the
Egr-1
gene. Generation of mice carrying a null mutation in the Egr-1
gene
by Dr Jeff Milbrandt and colleagues (Lee et al
21 )
have provided
a valuable research tool to gain important insights into
the
functions of Egr-1 in vivo. Although no observable developmental
or
behavioral defects have been reported to date,
21 female
homozygotes
are incapable of reproduction.
22 These
mice have low or undetectable
levels of LH-ß mRNA and protein,
whereas levels of follicle-stimulating
hormone-ß and prolactin or
receptors for gonadotropin-releasing
hormone and type II activin are
not attenuated. The lack of
LH-ß expression in knockout mice is due
to inactivity
of the LH-ß promoter by virtue of a single conserved
Egr-1
binding site in the proximal region.
22
Analysis of these animals
may provide direct links between
Egr-1 and specific target genes.
It will be interesting to determine
whether PDGF-A, PDGF-B,
TGF-ß
1, u-PA, and tissue factor
activation at the wound
edge after endothelial
denudation is compromised in this animal
model. Although
provocative if this analysis suggests a
relationship,
phenotypic analysis of these mice is complicated
by the potential
functional redundancy contributed by related members
of the
Egr family.
 |
Activation of Egr-1 Itself
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The intracellular signaling pathways underlying the inducible
expression
of Egr-1 involve cooperative interactions between SRF and
TCFs,
such as Elk-1 and SAP-1, at SREs in the Egr-1 promoter. Our
present
knowledge on these regulatory processes is based mainly on
insights
obtained from studies on the c-
fos
promoter,
23 where a quaternary
complex composed of two
molecules of TCF and two molecules of
SRF forms over the
SRE.
24 Elk-1 and SAP-1 are both substrates
of
phosphorylation by members of the
mitogen-activated kinase
superfamily, JNK and
ERK.
25 ERK-1/2 and JNK-1 are rapidly activated
in
endothelial cells after mechanical injury or upon
exposure
to FGF-2 or PMA (L.M. Khachigian, unpublished data, 1997).
These
kinases are also activated in endothelial
cells exposed to physiological
levels of fluid
shear stress.
26 27 Thus, it appears that diverse
biochemical
and fluid biomechanical stimuli activate Egr-1 and
Egr-1dependent
expression by triggering distinct signaling pathways
that converge
at the Egr-1 promoter (Figure

).
 |
Negative Regulation of PDGF and Egr-1
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The PDGF-A and PDGF-B promoters are also subject to negative
transcriptional
regulation. The Wilms' tumor suppressor gene encodes a
zinc-finger
DNA binding protein, WT-1, that interacts with the
Egr-1/Sp1
binding site in the PDGF-A promoter.
28 29
Transient cotransfection
studies have determined that WT-1 serves as a
potent repressor
of PDGF-A transcription.
28 29 Although it
is not known whether
the inhibitory activity of WT-1
involves the displacement of
prebound Sp1 or Egr-1 from the promoter in
intact cells, we
have shown this to be the case with recombinant
proteins (L.M.
Khachigian and T. Collins, unpublished data, 1997).
Interestingly,
WT-1 does not appear to bind to the PDGF-B promoter.
Whether
an inverse proportional relationship exists between the
expression
of PDGF-A and WT-1 in vascular cells is not yet known.
Varying
levels of PDGF-A expression in different cell types, or the
magnitude
and duration of its induction, may be influenced by the
constitutive
or mutable expression of transcriptional repressors, such
as
WT-1.
Two corepressors of Egr-1, NAB130 and NAB2,31
have been identified. These factors inhibit the activity of Egr-1 by
direct protein-protein interactions, supporting earlier findings that
deletion of certain peptide regions in the Egr-1 molecule actually
increases transcriptional activity by
10-fold.32 33
Whereas NAB1 is constitutively expressed, NAB2 is stimulated by known
inducers of Egr-1, such as serum and growth factors. This raises the
intriguing possibility that NAB-like factors mediate the postinduction
transcriptional repression of PDGF and other Egr-1dependent
genes.
The processes of cell movement and proliferation following mechanical
injury are preceded by acute changes in gene expression. Multiple
studies have correlated vascular remodeling with the inducible
expression of PDGF and other genes. Although we have only begun to
dissect the transcriptional mechanisms mediating these events, this
Mini Review illustrates that positive transcriptional activation by
Egr-1 may be a key to the inducible expression of PDGF and perhaps
multiple other pathophysiologically relevant
genes in cells of the vessel wall.
 |
Selected Abbreviations and Acronyms
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| ERK |
= |
extracellular regulated kinase |
| FGF-2 |
= |
fibroblast growth factor-2 |
| JNK |
= |
c-Jun N-terminal kinase |
| LH-ß |
= |
luteinizing hormone-ß |
| PDGF |
= |
platelet-derived growth factor |
| PMA |
= |
phorbol 12-myristate 13-acetate |
| SRE |
= |
serum response element |
| SRF |
= |
ternary complex factors |
| SSRE |
= |
shear-stress response element |
| TCF |
= |
ternary complex factor |
| TGF-ß1 |
= |
transforming growth factor-ß1 |
TNF- |
= |
tumor necrosis factor- |
| u-PA |
= |
urokinase-type plasminogen activator |
|
 |
Acknowledgments
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Dr Khachigian holds an R. Douglas Wright Research Fellowship
from
the National Health and Medical Research Council of Australia,
and
Dr Collins is supported by grants RO1 HL-35716, HL-45462,
and PO1
HL-36028 from the National Institutes of Health. The
authors regret
that space limitations have precluded a comprehensive
citation of all
relevant primary publications.
Received June 18, 1997;
accepted July 30, 1997.
 |
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