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Commentary |
From the Pulmonary and Critical Care Division,*
Department of Medicine and the Vascular Research
Division,
Department of Pathology, Brigham and
Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Introduction |
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 Top Introduction References |
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In this issue of the American Journal of Pathology, Santiago et al have added another component in the complex chain of molecular events linking endothelial cell injury and growth factor induction.1 These observations revolve around an inducible transcriptional factor called the "early growth response factor-1" (Egr-1).2 Evidence is accumulating to suggest that Egr-1 is involved in the regulation of multiple genes within diverse organ systems through protein-protein interactions with protein kinases and other transcription factors. Indeed, Egr-1 and its role in transcription regulation has potential relevance to the pathogenesis of a variety of vascular diseases. Egr-1-mediated gene transcription and its possible role in vascular disease will be reviewed here.
Egr-1,3
also known as nerve growth factor
induced-A (NGFI-A),4
krox-24, ZIF268, and TIS8,
is an 80- to 82-kd protein consisting of 533 amino acids, discovered
independently by a number of laboratories searching for factors
regulating cell growth and proliferation.2,5
It
is the prototype of a family of zinc-finger transcription factors that
includes Egr-2, Egr-3, Egr-4, and NGFI-B. Egr-1 is an example of an
"immediate-early response protein" because it is rapidly and
transiently induced by a large number of growth factors, cytokines, and
injurious stimuli.2
Egr-1 contains a DNA binding
domain consisting of three zinc fingers which are located between amino
acids 332 to 416 toward the carboxy-terminal region of the protein.
Through these zinc fingers Egr-1 binds specifically to the major
groove of DNA at commonly encountered G+C-rich DNA sequences
containing the consensus binding code GCG(T/G)GGGCG. Once bound to DNA,
Egr-1 alters gene transcription through mechanisms dependent on both
coactivators and corepressors. Mutational studies have identified a
strong transcription activation zone within the amino-terminal region
of the protein between amino acids 1 and 281.2
Transcriptional coactivators, such as CREB-binding protein (CBP) and
p300, can interact directly with the activation region of Egr-1 and
increase Egr-1 trans-activation.6
However, these interactions are relatively weak compared with some
sequence-specific transcription factors, such as the p65 (Rel A)
component of NF-
B, and their role in authentic Egr-1-mediated gene
expression remains unclear.6
Corepressors such as NGFI-A-binding proteins 1 and 2 (NAB1 and NAB2) negatively regulate Egr-1 activity. NAB1 was identified using a yeast two-hybrid system by its ability to bind a 34-aa inhibitory domain of Egr-1, called R1, located 5' of the zinc finger binding domain.7,8 Deletion of R1 results in a marked increase in Egr-1 transcriptional activity and overexpression of NAB1 markedly decreases Egr-1 transcriptional activity. The related protein NAB2 was subsequently discovered because of its strong homology to NAB1.9 NAB2 functions similarly to NAB1; however, there are important differences between these related proteins. For example, NAB1 is constitutively expressed in most cell types, whereas NAB2 is rapidly and transiently induced by many of the same stimuli that induce Egr-1. Furthermore, the pattern of tissue expression for NAB2 seems to be more tissue-selective than NAB1. Because of these differences NAB2 may play a negative feedback role by down-regulating the burst of Egr-1 activity that accompanies mitogenic, differentiative, or noxious stimuli. Although the mechanism of action of these inhibitors is unknown, it is tempting to speculate that they interfere with Egr-1's ability to bind coactivators such as CBP or p300.
It has been hypothesized that Egr-1 may play a key regulatory role by
linking injurious stimuli to the induction of genes directing the
expression of effector molecules that ultimately result in vascular
pathology.10
Egr-1 is inducibly expressed in many
different cell types; among the vascular cells known to express Egr-1
are endothelial cells, smooth muscle cells, fibroblasts, and
leukocytes. Many stimuli associated with the development of vascular
diseases, including shear stress, mechanical injury, platelet-derived
growth factors (PDGF), hypoxia, reactive oxygen species, angiotensin
II, and acidic fibroblast growth factor (FGF-1), are capable of
inducing Egr-1 in tissue culture and, in some cases, in authentic blood
vessels.10,11
Santiago et al have provided
compelling evidence to suggest that basic fibroblast growth factor
(FGF-2) be included in this list of important mediators regulating
Egr-1 expression in endothelial cells following
injury.1,11
They demonstrate that Egr-1 induction
by injury involves liberation and paracrine activity of
FGF-21
(Figure 1)
.
This growth factor rapidly activates signal transduction pathways
involving the mitogen-activated protein kinases (MAPKs) that converge
at the Egr-1 promoter. The authors also show that Egr-1 plays a
necessary role in the reparative response of endothelial injury. These
signaling events may underlie the pathogenesis of intravascular lesions
following conventional coronary intervention in
humans.12
|
. Santiago et
al have shown that at least some of these events are activated
following mechanical injury to cultured endothelium in an endogenous
FGF-2-dependent manner.1
It is possible that
protein kinases involved in the induction of Egr-1 transcription may
also affect Egr-1's phosphorylation state and alter its ability to
bind other proteins, as well as DNA. FGF-2's ability to induce Egr-1 is also noteworthy because it appears to be a factor responsible for a significant portion of Egr-1 production by endothelial cells after mechanical injury. If these findings hold true in authentic blood vessels, FGF-2 may represent a narrow focal point for a therapeutic intervention that breaks the cycle of injury-induced vascular proliferation that leads to lesion formation. However, in vivo, it is possible that other important factors and parallel pathways are involved, with perhaps several stimuli acting in an additive, synergistic, or inhibitory fashion to alter Egr-1 levels beyond those achievable by any single factor alone. In this regard, the role of the Egr-1 corepressors NAB1 and NAB2 in this context remains unknown. NAB2 is present in vascular endothelial cells and smooth muscle cells, and increases in response to injury closely following Egr-1 up-regulation [E.S. Silverman and T. Collins, unpublished data]. The time course suggests that NAB2 plays a role in modulating or counterbalancing the effect of increasing Egr-1 levels.
Following vascular cell activation or injury, Egr-1 is expressed
primarily in the nucleus of cells and is capable of altering the
transcription of several genes implicated in the pathogenesis of
vascular disease, including PDGF-A,15,16
PDGF-B,11
FGF-2,17
apolipoprotein A1,18
macrophage
colony-stimulating factor (M-CSF),19
TNF-
,20
tissue
factor,21
urokinase-type plasminogen activator
(u-PA),22
interleukin-2
(IL-2),23
intracellular adhesion molecule-1
(ICAM-1),24
copper-zinc superoxide dismutase gene
(SOD1),25
p53,26
thrombospondin,27
CD44,28
and 5-lipoxygenase (5-LO).29
All of these genes
contain one or more Egr-1 consensus binding site within their promoter
regions. Because many of these gene products also stimulate the
expression of Egr-1, autocrine or paracrine loops within blood vessels
are possible. These positive feedback loops serve to amplify and
sustain gene transcription through Egr-1-mediated mechanisms. For
example, PDGF A-chain and FGF can stimulate expression of Egr-1 and the
increased Egr-1 can activate PDGF A-chain or FGF transcription,
completing the amplification cycle.16,30,31
The role of Egr-1 in the regulation of authentic genes in vivo remains to be determined. Most of the studies demonstrating Egr-1 inducibility have involved transient transfection analysis of cells using promoter-reporter constructs of genes suspected of being Egr-1 targets. However, promoter-reporter constructs can behave differently from authentic promoters in the context of other regulatory elements and chromatin. To our knowledge, the only genes definitively linked to Egr-1 expression in vivo have been luteinizing hormone-ß (LH-ß), tissue factor, and apoprotein A-I genes, based on studies using the Egr-1 knockout mouse developed by J. Milbrandt and colleagues.32 For example, the human LH-ß promoter contains two functional Egr-1 binding sites in the proximal promoter region. In vivo support of these observations is the finding that female homozygous Egr-1 null mice are infertile as a result of luteinizing hormone deficiency.33 Another example with special relevance from a vascular perspective involves the tissue factor gene. The tissue factor promoter contains a serum response region that binds Egr-1 and activates transcription in vitro in response to hypoxia.21 In contrast to wild-type mice, mice deficient in Egr-1 fail to produce tissue factor, nor do they deposit fibrin in the pulmonary vasculature under hypoxic conditions. These findings strongly suggest a role for Egr-1 in the transcriptional regulation of tissue factor in authentic blood vessels.34 The final example of Egr-1's transcriptional effects in vivo involves the apoprotein A-1 gene. In a mouse model of nephrotic syndrome, levels of apoprotein A-1 in Egr-1 null mice were half those of the wild-type mice.35 Future studies involving these mice are likely to be particularly useful for identifying the roles of Egr-1 in an authentic biological system. However, attempts to demonstrate Egr-1-mediated transcription may be confounded by redundancy within the Egr family of transcription factors such that, in the absence of Egr-1, changes in gene expression may not be overtly manifested because related transcription factors may substitute and fulfill similar transcriptional roles. Therefore, in the absence of observable changes in transcription, one may not conclude that Egr-1 has no role in the transcriptional regulation of a given gene.
Egr-1's potential involvement in the pathogenesis of vascular disease was first recognized by Khachigian et al through promoter analysis of the PDGF A-chain and B-chain genes in endothelial cells, and represents the first link between a transcription factor and a target gene in the context of vascular injury.36 PDGFs are among the most potent mitogens and chemotaxins secreted by endothelial cells and vascular smooth muscle cells. Elevated levels of PDGFs are found in atheroscerotic plaques and are an important link between endothelial injury and the resulting fibroproliferative response that leads to atherosclerosis.37,38 In an effort to understand the regulation of PDGFs as they relate to the pathogenesis of vascular disease, the promoter sequences were cloned and studied in endothelial cells. The human PDGF A-chain and B-chain gene promoters are highly G+C-rich, contain a TATA box, and have a single transcriptional start site.39,40 The A-chain promoter is hypersensitive to cleavage by S1 nuclease and contains two overlapping Egr-1 binding sites between -71 and -50 bp from the transcription start site.41 The B-chain promoter has a cryptic Egr-1 site located -30 to -19 bp from the transcription initiation site. Transient transfection analysis using promoter-reporter constructs containing deletions of the A- and B-chain promoters have determined that the G+C-rich regions are essential for promoter activity and inducibility in endothelial cells.11,15 Phorbol ester 12-myristate 13-acetate (PMA) was the initial model agonist used to stimulate Egr-1 expression; however, these observations have subsequently been extended to several more pathophysiologically relevant stimuli such as mechanical injury, shear stress, and growth factors.31,42 These G+C-rich promoter regions are capable of binding recombinant Egr-1 and purified Egr-1 from nuclear extracts of stimulated endothelial cells and vascular smooth muscle cells. Moreover, Egr-1 up-regulation in endothelial cells can significantly activate promoter-reporter constructs above basal levels. Inhibition of Egr-1 or modification of the consensus binding site mitigates promoter activation. These findings have been extended to vascular smooth muscle cells, which are known to be another important source of some PDGFs in blood vessels.16,43 The role of the Egr-1 transcriptional pathway in authentic blood vessels is less clear. Although mechanical denudation of the endothelial lining of rat aortae leads to increased endothelial and smooth muscle Egr-1 expression before increased PDGF A-chain and B-chain expression, the causal association between Egr-1 and PDGF expression in vivo remains to be definitively proven.11,16 The list of Egr-1 target genes includes not only growth and coagulation factors, but proteins that could influence growth retardation and cell survival. By stimulating the expression of the gene for TGF-ß, Egr-1 may suppress growth of damaged endothelial cells. Additionally, induction of TGF-ß may hinder leukocyte recruitment, modulate vascular tone, and increase expression of growth factors such as PDGF.44 Injury-induced Egr-1 may also activate p53 via the Egr-1 site in its promoter. Induction of p53 genes associated with cell cycle arrest may provide modestly injured endothelial cells with the opportunity to respond to the injury. Lethally injured endothelial cells could be eliminated by induction of p53-dependent apoptotic genes, or by down-regulation of expression of bcl-2.45 Determining the balance between Egr-1-dependent growth factors and those proteins involved in survival may play a key role in the cellular events associated with vascular injury. Again, future studies using Egr-1 knockout mice or transgenic mice overexpressing Egr-1 within vascular cells may help elucidate the significance of these possibilities in vivo, as they have for LH-ß, tissue factor, and apoprotein A1.
The effect of Egr-1 on the enhancement or repression of reporter-gene transcription depends not only on the arrangement of DNA binding motifs within the promoter, but the cell type and nuclear milieu being studied.5 Possible explanations include: 1) Egr-1's ability to act in concert with multiple sequence-specific transcription factors; 2) variations in Egr-1's ability to interact with transcriptional coactivators such as CBP/p300; 3) variations in Egr-1's ability to interact with transcriptional corepressors such as NAB2; and 4) altered states of phosphorylation that affect Egr-1's ability to interact with proteins or DNA. It is the sum of all of the transcriptional components and their phosphorylation status that ultimately determines the effect of Egr-1 on a specific promoter.
Egr-1's ability to interact with other DNA binding proteins has
particular relevance to vascular biology. These interactions may occur
at one binding site in a gene; they may occur at mutually exclusive
binding sites in the gene; or they may occur directly via
protein-protein interactions in the absence of DNA. Of all these
mechanisms, displacement by Egr-1 at overlapping Egr-1/Sp1 consensus
binding sites, also termed Egr-1 displacement of Sp1, has been most
thoroughly described in vascular systems10,11,15
(Figure 1)
. In this regard, Egr-1 shares similar consensus binding
sites with transcription factors Sp1 (-GGGCGG-) and Wilm's tumor
suppressor, WT1 (-GNGNGGGNG-). In contrast to Egr-1 and WT1, Sp1 is a
ubiquitous zinc finger protein expressed in nearly all cell types and
is required for the expression of many essential genes. In general,
highest levels of Sp1 expression are found in cells undergoing
differentiation, and these high levels of Sp1 may be required for the
subsequent induction of tissue-specific genes.46
WT1 has the properties of a tumor suppressor gene and is expressed
predominantly in the kidney and genital organs where it plays an
important role in development.47
Many promoters
contain overlapping Egr-1, Sp1, and WT1 consensus binding
sites.5
In vitro studies using
recombinant proteins suggest that these transcription factors can
displace one another from many promoters, and binding site occupancy is
dependent on an equilibrium determined by their concentration within
the nucleus and affinity for the binding site. Sp1 is a relatively weak
activator of PDGF A-chain and B-chain transcription and is responsible
for basal levels of gene transcription in quiescent cultured
endothelial cells.48
When Egr-1 is up-regulated
by injury or growth factors it may displace Sp1 from the A-chain
promoter and increase transcription.15
Egr-1's
ability to augment transcription above levels mediated by Sp1 may
relate to its ability to interact with the transcriptional coactivator
CBP/p300. Unlike Egr-1, Sp1 does not interact with CBP/p300 but
directly with components of the basal transcription
apparatus.6
Sp1 may also have a structural role
in transcription by maintaining chromatin in an accessible
conformation.46
Regardless of its mechanism of
action, Sp1 appears to initiate transcription in a less efficient
manner than Egr-1 in endothelial cells. It is conceivable, however,
that Egr-1 may not always be an activator of transcription by this
mechanism. If CBP/p300 is unavailable to interact with DNA bound Egr-1,
due to sequestration or occupancy of binding sites by other
transcription factors, the result of Egr-1 displacement of Sp1 could be
transcription repression. In contrast to Egr-1 and Sp1, WT1 is a strong
inhibitor of PDGF A-chain promoter-reporter gene expression and may
function by occupying the G+C-rich promoter region and prevent Egr-1 or
Sp1 from binding.49
However, WT has not been
demonstrated to regulate the corresponding gene, and it is unlikely to
have a general role in vascular disease given its limited tissue
distribution. This raises the possibility that other WT-like
transcription factors may exist that play a role in the negative
regulation of these genes.
The number and relative positions of the Egr-1 consensus binding sites
are also essential determinants of Egr-1's ability to activate gene
transcription. This is true among different genes and within the same
gene among different individuals. Studies involving the 5-lipoxygenase
gene promoter illustrate this point. The wild-type human 5-LO gene
promoter contains 5 tandem Egr-1 consensus binding sites that bind
Egr-1 in vitro.50
In transfection
studies, the promoter-reporter constructs respond to overexpression of
Egr-1 and these 5 tandem Egr-1 sites are essential for
inducibility.29
An interesting development in
Egr-1-mediated transcription was the recent discovery of a family of
naturally occurring promoter mutations within the human 5-LO gene by In
et al.51
These mutations are characterized by a
variable number of tandem Egr-1 binding sites, from 3 to 6 sites for
each allele. The frequency of mutant alleles was quite high in a sample
of normal subjects, ranging from 2 to 18% depending on the particular
mutation; the wild-type allele was found in 76% of subjects. These
promoter mutations are capable of altering Egr-1 binding and reporter
gene transcription such that the intensity of binding and degree of
trans-activation are proportional to the number of consensus
binding sites.29
It has been hypothesized that
this is due to Egr-1's ability to interact with CBP/p300 through
multiple protein-protein contact points6
(Figure 1)
. The greater the number of binding sites, the more stable is the
platform for the recruitment of CBP/p300 and the greater is the effect
on transcription activation. The effect of these promoter mutations on
the expression of 5-LO in vivo is unknown at this time but
is the subject of intense investigation. A similar phenomenon of
genetic variability may relate to other promoters with multiple and
variably spaced Egr-1 consensus binding sites.
There is ample evidence to suggest that Egr-1 functions in concert with
other sequence-specific transcription factors binding to different
sites that are appropriately spaced within the promoter; however, their
role in vascular biology is less clear. For example, Egr-1 and the
steroidogenic factor-1 can bind to different regions of the LH-ß
subunit gene promoter and synergistically increase
transcription.52
Egr-1 may also interact
synergistically with the p65 protein to regulate transcription
of the NF-B1 (p50) gene.53
Finally, Egr-1 may
act synergistically with nuclear factor of activated T cells (NFAT) to
augment IL-2 transcription.54
Because some of
these transcription factors are known to interact directly with
CBP/p300, it is possible that together with Egr-1 they facilitate
transcription by further stabilizing CBP/p300 at the promoter. Direct
protein-protein interactions between sequence-specific transcription
factors in the absence of DNA are also possible but less well
documented. A study by Jain et al suggests that Egr-1 and Sp1 may bind
directly to one another depending on Egr-1's phosphorylation status as
regulated by the casein kinase II-dependent phosphorylation
pathway.55
Bound together, they may effectively
sequester each other and mitigate binding to gene
promoters.56
Phosphorylated Egr-1 binds less
avidly to Sp1, resulting in higher levels of free transcription factor
and the ability to interact with promoters.
Following vascular injury, a series of cellular changes takes place in the vessel wall that can result in the development of pathology. These events are preceded by the inducible expression of a series of genes in endothelial cells. Although we have only begun to dissect the signaling pathways activated by vascular injury, it appears that Egr-1 may play a key role in these initial changes. Egr-1 can be activated by multiple mechanisms, including injury-induced release and paracrine activation by FGF-2, as outlined in the paper by Santiago and coworkers.1 Additionally, Egr-1 can activate several key groups of pathophysiologically relevant target genes, including growth and coagulation factors, cell surface adhesion molecules, and proteins that can alter cell survival. However, induction of Egr-1 and subsequent Egr-1-mediated transcription are complex processes and not a simple "on-off" switch, as sometimes perceived.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants K08 HL03827 to E.S.S. and R01 HL35716 to T.C.
Accepted for publication January 15, 1999.
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References |
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TopIntroductionReferences |
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S. Leung-Theung-Long, E. Roulet, P. Clerc, C. Escrieut, S. Marchal-Victorion, B. Ritz-Laser, J. Philippe, L. Pradayrol, C. Seva, D. Fourmy, et al. Essential Interaction of Egr-1 at an Islet-specific Response Element for Basal and Gastrin-dependent Glucagon Gene Transactivation in Pancreatic {alpha}-Cells J. Biol. Chem., March 4, 2005; 280(9): 7976 - 7984. [Abstract] [Full Text] [PDF]
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 M. F. Banks, E. V. Gerasimovskaya, D. A. Tucker, M. G. Frid, T. C. Carpenter, and K. R. Stenmark Egr-1 antisense oligonucleotides inhibit hypoxia-induced proliferation of pulmonary artery adventitial fibroblasts J Appl Physiol, February 1, 2005; 98(2): 732 - 738. [Abstract] [Full Text] [PDF]
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V. Korcheva, J. Wong, C. Corless, M. Iordanov, and B. Magun Administration of Ricin Induces a Severe Inflammatory Response via Nonredundant Stimulation of ERK, JNK, and P38 MAPK and Provides a Mouse Model of Hemolytic Uremic Syndrome Am. J. Pathol., January 1, 2005; 166(1): 323 - 339. [Abstract] [Full Text] [PDF]
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P. Schalch, G. Patejunas, M. Retuerto, S. Sarateanu, J. Milbrandt, G. Thakker, D. Kim, J. Carbray, R. G. Crystal, and T. K. Rosengart Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: Evidence for a central role in vascular homeostasis J. Thorac. Cardiovasc. Surg., October 1, 2004; 128(4): 595 - 601. [Abstract] [Full Text] [PDF]
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 S. Malkani, K. J. Wallace, M. P. Donley, and J. B. Rosen An egr-1 (zif268) Antisense Oligodeoxynucleotide Infused Into the Amygdala Disrupts Fear Conditioning Learn. Mem., September 1, 2004; 11(5): 617 - 624. [Abstract] [Full Text] [PDF]
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 D. Rahmutula, J. Cui, S. Chen, and D. G. Gardner Transcriptional Regulation of Type B Human Natriuretic Peptide Receptor Gene Promoter: Dependence on Sp1 Hypertension, September 1, 2004; 44(3): 283 - 288. [Abstract] [Full Text] [PDF]
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 C. G. Lee, S. J. Cho, M. J. Kang, S. P. Chapoval, P. J. Lee, P. W. Noble, T. Yehualaeshet, B. Lu, R. A. Flavell, J. Milbrandt, et al. Early Growth Response Gene 1-mediated Apoptosis Is Essential for Transforming Growth Factor {beta}1-induced Pulmonary Fibrosis J. Exp. Med., August 2, 2004; 200(3): 377 - 389. [Abstract] [Full Text] [PDF]
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M. Shozu, K. Murakami, T. Segawa, T. Kasai, H. Ishikawa, K. Shinohara, M. Okada, and M. Inoue Decreased Expression of Early Growth Response-1 and Its Role in Uterine Leiomyoma Growth Cancer Res., July 1, 2004; 64(13): 4677 - 4684. [Abstract] [Full Text] [PDF]
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 M. M. M. Abdel-Latif, H. J. Windle, K. A. Fitzgerald, Y. S. Ang, D. N. Eidhin, M. Li-Weber, K. Sabra, and D. Kelleher Helicobacter pylori Activates the Early Growth Response 1 Protein in Gastric Epithelial Cells Infect. Immun., June 1, 2004; 72(6): 3549 - 3560. [Abstract] [Full Text] [PDF]
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S. Y. Ahn, C.-H. Cho, K.-G. Park, H. J. Lee, S. Lee, S. K. Park, I.-K. Lee, and G. Y. Koh Tumor Necrosis Factor-{alpha} Induces Fractalkine Expression Preferentially in Arterial Endothelial Cells and Mithramycin A Suppresses TNF-{alpha}-Induced Fractalkine Expression Am. J. Pathol., May 1, 2004; 164(5): 1663 - 1672. [Abstract] [Full Text] [PDF]
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J. Hjoberg, L. Le, A. Imrich, V. Subramaniam, S. I. Mathew, J. Vallone, K. J. Haley, F. H. Y. Green, S. A. Shore, and E. S. Silverman Induction of early growth-response factor 1 by platelet-derived growth factor in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L817 - L825. [Abstract] [Full Text] [PDF]
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 J. B. Rosen The Neurobiology of Conditioned and Unconditioned Fear: A Neurobehavioral System Analysis of the Amygdala Behav Cogn Neurosci Rev, March 1, 2004; 3(1): 23 - 41. [Abstract] [PDF]
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 C. Pipaon, J. A. Casado, J. A. Bueren, and J. L. Fernandez-Luna Jun N-terminal kinase activity and early growth-response factor-1 gene expression are down-regulated in Fanconi anemia group A lymphoblasts Blood, January 1, 2004; 103(1): 128 - 132. [Abstract] [Full Text] [PDF]
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P. Sartipy and D. J. Loskutoff Expression Profiling Identifies Genes That Continue to Respond to Insulin in Adipocytes Made Insulin-resistant by Treatment with Tumor Necrosis Factor-{alpha} J. Biol. Chem., December 26, 2003; 278(52): 52298 - 52306. [Abstract] [Full Text] [PDF]
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 B. Martin-McNulty, D. M. Tham, V. da Cunha, J. J. Ho, D. W. Wilson, J. C. Rutledge, G. G. Deng, R. Vergona, M. E. Sullivan, and Y.-X. Wang 17{beta}-Estradiol Attenuates Development of Angiotensin II-Induced Aortic Abdominal Aneurysm in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1627 - 1632. [Abstract] [Full Text] [PDF]
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 A. Haider, I. Lee, J. Grabarek, Z. Darzynkiewicz, and N. R. Ferreri Dual Functionality of Cyclooxygenase-2 as a Regulator of Tumor Necrosis Factor-Mediated G1 Shortening and Nitric Oxide-Mediated Inhibition of Vascular Smooth Muscle Cell Proliferation Circulation, August 26, 2003; 108(8): 1015 - 1021. [Abstract] [Full Text] [PDF]
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R. N. Hasan, S. Phukan, and S. Harada Differential Regulation of Early Growth Response Gene-1 Expression by Insulin and Glucose in Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 988 - 993. [Abstract] [Full Text] [PDF]
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R. K. Giri, S. K. Selvaraj, and V. K. Kalra Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA J. Immunol., May 15, 2003; 170(10): 5281 - 5294. [Abstract] [Full Text] [PDF]
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L. Tan, H. Peng, M. Osaki, B. K. Choy, P. E. Auron, L. J. Sandell, and M. B. Goldring Egr-1 Mediates Transcriptional Repression of COL2A1 Promoter Activity by Interleukin-1beta J. Biol. Chem., May 9, 2003; 278(20): 17688 - 17700. [Abstract] [Full Text] [PDF]
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H. Fujino, W. Xu, and J. W. Regan Prostaglandin E2 Induced Functional Expression of Early Growth Response Factor-1 by EP4, but Not EP2, Prostanoid Receptors via the Phosphatidylinositol 3-Kinase and Extracellular Signal-regulated Kinases J. Biol. Chem., March 28, 2003; 278(14): 12151 - 12156. [Abstract] [Full Text] [PDF]
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I. Manabe, T. Shindo, and R. Nagai Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy Circ. Res., December 13, 2002; 91(12): 1103 - 1113. [Abstract] [Full Text] [PDF]
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M. Fu, J. Zhang, Y. Lin, X. Zhu, M. U. Ehrengruber, and Y. E. Chen Early Growth Response Factor-1 Is a Critical Transcriptional Mediator of Peroxisome Proliferator-activated Receptor-gamma 1 Gene Expression in Human Aortic Smooth Muscle Cells J. Biol. Chem., July 19, 2002; 277(30): 26808 - 26814. [Abstract] [Full Text] [PDF]
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V. N. Bochkov, D. Mechtcheriakova, M. Lucerna, J. Huber, R. Malli, W. F. Graier, E. Hofer, B. R. Binder, and N. Leitinger Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT Blood, January 1, 2002; 99(1): 199 - 206. [Abstract] [Full Text] [PDF]
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 D. J. TSCHUMPERLIN and J. M. DRAZEN Mechanical Stimuli to Airway Remodeling Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S90 - 94. [Abstract] [Full Text] [PDF]
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L. J. Landesberg, R. Ramalingam, K. Lee, T. K. Rosengart, and R. G. Crystal Upregulation of transcription factors in lung in the early phase of postpneumonectomy lung growth Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1138 - L1149. [Abstract] [Full Text] [PDF]
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T. M. Lincoln, N. Dey, and H. Sellak Signal Transduction in Smooth Muscle: Invited Review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression J Appl Physiol, September 1, 2001; 91(3): 1421 - 1430. [Abstract] [Full Text] [PDF]
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E. S. SILVERMAN, G. T. DE SANCTIS, J. BOYCE, J. A. MACLEAN, A. JIAO, F. H. Y. GREEN, H. GRASEMANN, D. FAUNCE, G. FITZMAURICE, G.-P. SHI, et al. The Transcription Factor Early Growth-response Factor 1 Modulates Tumor Necrosis Factor-{alpha}, Immunoglobulin E, and Airway Responsiveness in Mice Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 778 - 785. [Abstract] [Full Text] [PDF]
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 S. E. Bell, A. Mavila, R. Salazar, K. J. Bayless, S. Kanagala, S. A. Maxwell, and G. E. Davis Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling J. Cell Sci., January 8, 2001; 114(15): 2755 - 2773. [Abstract] [Full Text] [PDF]
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 J. C. Tsai, L. Liu, J. Guan, and W. C. Aird The Egr-1 gene is induced by epidermal growth factor in ECV304 cells and primary endothelial cells Am J Physiol Cell Physiol, November 1, 2000; 279(5): C1414 - C1424. [Abstract] [Full Text] [PDF]
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L. Liu, J. C. Tsai, and W. C. Aird Egr-1 gene is induced by the systemic administration of the vascular endothelial growth factor and the epidermal growth factor Blood, September 1, 2000; 96(5): 1772 - 1781. [Abstract] [Full Text] [PDF]
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F. Vidal, J. Aragones, A. Alfranca, and M. O. de Landazuri Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1 Blood, June 1, 2000; 95(11): 3387 - 3395. [Abstract] [Full Text] [PDF]
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J. M. Miano and B. C. Berk NAB2: A Transcriptional Brake for Activated Gene Expression in the Vessel Wall? Am. J. Pathol., October 1, 1999; 155(4): 1009 - 1012. [Full Text] [PDF]
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E. S. Silverman, L. M. Khachigian, F. S. Santiago, A. J. Williams, V. Lindner, and T. Collins Vascular Smooth Muscle Cells Express the Transcriptional Corepressor NAB2 in Response to Injury Am. J. Pathol., October 1, 1999; 155(4): 1311 - 1317. [Abstract] [Full Text] [PDF]
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T. L. Haas, D. Stitelman, S. J. Davis, S. S. Apte, and J. A. Madri Egr-1 Mediates Extracellular Matrix-driven Transcription of Membrane Type 1 Matrix Metalloproteinase in Endothelium J. Biol. Chem., August 6, 1999; 274(32): 22679 - 22685. [Abstract] [Full Text] [PDF]
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J. Svaren, T. Ehrig, S. A. Abdulkadir, M. U. Ehrengruber, M. A. Watson, and J. Milbrandt EGR1 Target Genes in Prostate Carcinoma Cells Identified by Microarray Analysis J. Biol. Chem., December 1, 2000; 275(49): 38524 - 38531. [Abstract] [Full Text] [PDF]
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