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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3199-3203
IMMUNOBIOLOGY
RasGRP links T-cell receptor signaling to Ras
Julius O. Ebinu,
Stacey L. Stang,
Christine Teixeira,
Drell A. Bottorff,
Jonathan Hooton,
Peter M. Blumberg,
Michele Barry,
R. Chris Bleakley,
Hanne L. Ostergaard, and
James C. Stone
From the Departments of Biochemistry and Immunobiology, University
of Alberta, Edmonton, Alberta, Canada; and the Laboratory of
Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute,
Bethesda, MD.
 |
Abstract |
Stimulation of the T-cell receptor (TCR) alters a number of
intracellular signaling pathways including one that involves protein tyrosine kinases, phospholipase C- 1 (PLC-1), diacylglycerol (DAG), and calcium messengers. By a divergent pathway, TCR-stimulated protein tyrosine kinase activity is thought to result independently in
recruitment of the Ras activator Sos to the plasma membrane, leading to
Ras activation. Here we show that RasGRP, a Ras activator that contains
calcium-binding EF hands and a DAG-binding domain, is expressed in T
cells. A PLC-1 inhibitor diminished activation of Ras following TCR
stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited
increased RasGRP and increased Ras-guanyl nucleotide association
activity that was inhibited by antibodies directed against RasGRP.
Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and
augmented interleukin-2 secretion in response to calcium ionophore plus
DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP
links TCR and PLC-1 to Ras-Erk signaling, a pathway amenable to
pharmacologic manipulation.
(Blood. 2000;95:3199-3203)
© 2000 by The American Society of Hematology.
| |
Introduction |
A key step in T-cell activation is the physical
interaction between the T-cell receptor (TCR) on the surface of the T
cells and peptide antigen presented in the context of a major
histocompatibility molecule on an antigen-presenting cell. This
interaction results in the rapid modulation of several biochemical
processes within the T cells that ultimately lead to T-cell
proliferation.1-3 TCR-proximal events include the
activation of cytoplasmic protein tyrosine kinases such as the
CD4-associated protein tyrosine kinase lck. Tyrosine phosphorylation of
the intracellular domains of the small TCR subunits by lck leads to the
recruitment to the TCR of a second protein tyrosine kinase,
ZAP-70.4-6 TCR-associated ZAP-70 phosphorylates adaptor
proteins such as LAT and SLP-76, which may be complexed at the plasma
membrane.7-10
Within minutes of TCR stimulation, several divergent signaling systems
are thought to come into play. Phospholipase C-1 (PLC-1) is
activated by a combination of tyrosine phosphorylation and recruitment
to the tyrosine phosphorylated adaptor proteins.11 Cleavage
of membrane phosphoinositides by PLC-1 generates membrane diacylglycerol (DAG) messenger, which activates protein kinase C (PKC).
PLC-1 also generates inositol triphosphate, which facilitates a rise
in free cytoplasmic calcium, stimulation of the calcium-activated phosphatase calcineurin, and engagement of the nuclear factor of
activated T cells (NF-AT) transcription system.12
Independently, early protein tyrosine kinase activity is thought to
activate the small GTPase Ras by promoting the formation of Ras bound
to GTP. Ras-GTP activates the Raf-Mek-Erk protein kinase cascade and
this pathway controls the level of the Jun/Fos dimeric transcription
factor known as AP1.13 The coordinated activation of AP1
transcription factors by the Ras-Erk signaling system and the NF-AT
transcription factor results in efficient transcription of the
interleukin-2 (IL-2) gene, the protein product of which drives T-cell
proliferation.12 Additional signaling systems contribute to
the synthesis of the IL-2 receptor, changes in cell shape, and other
aspects of T-cell activation.14-16
Despite considerable effort, the mechanism whereby Ras is activated
after TCR stimulation has not been fully elucidated. In principle, the
equilibrium between the GDP-bound "off" and GTP-bound "on"
states of Ras could be regulated by controlling the rates of GTP
hydrolysis and guanyl nucleotide exchange. The hydrolysis reaction is
controlled by GTPase activating proteins (GAPs). The exchange rate is
limited by the activity of guanyl nucleotide exchange factors (GEFs).
Early work with T cells indicated that Ras activation following TCR
stimulation involved a PKC-dependent inhibition of Ras
GAPs.17-19 The ability of the DAG analogue phorbol ester
myristate (PMA) to activate Ras in T cells has also been attributed to
PKC-dependent inhibition of Ras GAPs. However, in most cell types, Ras
is positively regulated by the recruitment of Ras GEFs such as Sos to
the plasma membrane through tyrosine phosphorylated adaptor
proteins.20,21 The results from a number of studies suggest
that Sos may activate Ras in T cells by such a
mechanism.22-24
We recently described a novel Ras GEF called RasGRP (Ras guanyl
nucleotide releasing protein25). In addition to the
catalytic domain responsible for catalyzing nucleotide release, RasGRP
contains a pair of calcium-binding EF hands and a DAG-binding domain.
Treatment of engineered fibroblasts with PMA resulted in increased
association of RasGRP with membranes and Ras activation.25
Although normal expression was initially detected only in brain,
subsequent studies revealed that RasGRP RNA was expressed in a variety
of blood cells including T cells.26,27 These observations
led to the hypothesis that TCR stimulation, PLC-1 activity, and DAG
and possibly calcium messengers are linked by RasGRP to Ras-Erk signaling.
| |
Materials and methods |
Antibodies and plasmids
H176 is derived from rabbits immunized with the amino-terminal rat
RasGRP peptide (residues 1-15). J32 was raised in rabbits by injecting
the catalytic domain of rat RasGRP (residues 49-473); these antibodies
react with both rat and human RasGRP in an immunoblot protocol.
Antibodies were purified by affinity selection using immobilized
recombinant rat RasGRP. Full-length human RasGRP complementary DNA
(cDNA) was cloned into the SalI site of
pBMGNeo.28 The plasmid was introduced into Jurkat T
cells by electroporation and Neo+ cells were selected in 1 mg/mL G418.
Detection of RasGRP by immunoblotting
Protein lysates were prepared from various cell lines and from
thymocytes freshly isolated from the thymus of a 6-week-old female
Balb/c mouse. H176 was used in an immunoblot protocol with goat
antirabbit IgG conjugated to horseradish peroxidase and enhanced chemiluminescence detection (ECL kit, Pierce, Rockford, IL) to detect
p90 RasGRP (100 µg/mL total cellular protein per sample).
Ras activation assay
Ras activation was assayed by comparing the amount of Ras-GTP that
could be precipitated using GST-Raf fusion protein and the amount of
total Ras in cell lysates as described,29 with minor
modification. Jurkat were grown to 1 × 106/mL in
RPMI containing 10% heat-inactivated fetal bovine serum plus
penicillin and streptomycin. Cells were incubated in herbimycin A (1.0 µg/mL) for 18 hours. Alternatively, cells were treated with U73343 or
U73122 (1.0 µmol/L) for the last 15 minutes of incubation. Cells were
then concentrated by centrifugation, suspended in 1.0 mL of the
original medium in a plastic centrifuge tube
(5 × 106 cells/assay), and incubated at 37°C
for 5 minutes. After addition of OKT3 at 10 µg/mL or 0.156 µg/mL
for a further 5 minutes, the cells were immediately centrifuged at
1400g for 2 minutes at 4°C. (Note that soluble OKT3 was
used throughout these experiments.) Cell pellets were then lysed in 25 mmol/L HEPES pH 7.5, 150 mmol/L NaCl, 1.0% NP40, 10% glycerol, 25 mmol/L NaF, 10 mmol/L MgCl2, 1.0 mmol/L EDTA, and 1.0 mmol/L sodium ortho-vanadate plus protease inhibitors. After
centrifugation to remove nuclei, 90% of each supernatant was incubated
with GST-RAF (Ras-binding domain) fusion protein bound to glutathione
beads to collect GTP-bound Ras. Bead-associated Ras was detected using
an anti-K-ras antibody (Santa Cruz no. F234, Santa Cruz, CA) in an
immunoblotting protocol. The remaining 10% of each lysate was probed
with the anti-Ras antibody to verify that similar amounts of total Ras
were present in each lysate and with phospho-Erk antibody (New England
Biolabs no. 9101, Beverly, MA) to assess the level of Erk activation.
Inhibitors were purchased from Calbiochem (San Diego, CA).
Subcellular fractionation
Jurkat T cells were suspended in hypotonic buffer and disrupted in a
glass homogenizer.25 After removing nuclei and unbroken cells by centrifugation at 2000g, cell homogenates were
separated into P100 and S100 by ultracentrifugation at
100 000g. For detection of RasGRP, samples were resolved by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
and immunoblotted with H176 IgG.
Membrane Ras-guanyl nucleotide association assay
To assay guanyl nucleotide association with membrane-bound Ras,
membrane fractions were suspended in 20 mmol/L Tris pH 7.5, 100 mmol/L
NaCl, 1 mmol/L MgCl2 (2.5 × 105 cell
equivalents/µL). Membranes (25 µL) were then incubated with 1 µL
[ 32P]GTP (3000 Ci/mmol final concentration 66 nmol/L)
in a final volume of 50 µL. After incubation at 30°C for 1 minute
to allow exchange of resident guanyl nucleotide with the radiolabeled
GTP, the reaction was diluted in ice-cold buffer (50 mmol/L Tris pH 7.5, 150 mmol/L NaCl, 20 mmol/L MgCl2, 0.5% v/v NP40)
containing 1 µg anti-Ras antibody Y13-259. After incubation at
0°C for 1 hour, Ras-guanyl nucleotide complexes were recovered
using protein A-Sepharose beads coated with rabbit antirat IgG. Guanyl
nucleotide was released by heating at 80°C in 1.0 mol/L potassium
phosphate (pH 3.4). Following chromatography of polyethylenimine
plates, total guanyl nucleotide (GTP plus GDP) was quantified by
phosphor-imager analysis. Background values obtained when no Y13-259
antibody was present were used to correct the experimental values. To
determine the maximal degree of Ras activation in these preparations,
membranes were exposed to 5.0 mmol/L EDTA for 5 minutes at 30°C
followed by addition of excess MgCl2, before lysis and
precipitation. To demonstrate the specificity of the above assay,
membrane preparations were preincubated with antibodies (J32) raised
against the catalytic domain of RasGRP (residues 49-473) or with
preimmune antibodies from the same rabbit. To demonstrate that J32
antibodies specifically inhibited RasGRP, exchange assays were
performed with purified proteins in buffer containing 20 mmol/L Tris pH
7.5, 100 mmol/L NaCl, 1.0 mmol/L DTT, 1.0 mmol/L MgCl2,
10% v/v glycerol, and either 1.6 pmol recombinant full-length Sos or
1.96 pmol RasGRP catalytic domain. These low amounts of Ras GEF were
used to increase the likelihood that the antibody was in molar excess.
Total IgG was 62 pmol/reaction but the amount of neutralizing antibody
is an unknown fraction of the total.
IL-2 assays
Where indicated, cells were incubated with 5.0 µmol/L
CdCl2 for 24 hours to induce RasGRP expression from the
metallothionein promoter. Cells (5 × 105) of each
type were then exposed in 1.0 mL fresh medium to calcium ionophore and
DAG agonist for a further 48 hours. IL-2 in supernatants was measured
using a colorimetric cell survival bioassay using the IL-2-dependent
HT2 mouse T-cell line and units were defined as
described.30,31
| |
Results |
Using an antibody (H176) directed against the amino-terminal peptide
sequence of RasGRP, we documented expression of this Ras activator in a
variety of human and mouse T-cell lines, but not in other cell types
(Figure 1). RasGRP was also detected in primary mouse thymocytes. As controls, we showed that p90 RasGRP was
present in rat2 cells engineered to express human RasGRP cDNA, but not
in parental rat2 cells.
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| Fig 1.
RasGRP expressed in T cells.
Protein lysates were prepared from T-cell lines (T; Jurkat, human acute
T-cell leukemia; ADOH, mouse T-helper cell hybridoma; BW5147, mouse
T-cell lymphoma; SAKR, mouse T-cell lymphoma; EL4, mouse T-cell
lymphoma; CEM, human acute T-cell lymphoblastic leukemia; YT-INDY,
human NK-like T-cell leukemia; PEER, human T-cell lymphoblastic
leukemia; MOLT4, human acute lymphoblastic T-cell leukemia), and from
non-T-cell lines (non-T: FaDu, human pharynx squamous cell carcinoma;
B65, mouse neuroblastoma; ED27, human chroriocarcinoma; MCF10A, human
mammary epithelium; SK28 and WM39, human melanoma). Freshly isolated
mouse thymocyctes (Th) were also examined. As controls, we studied rat2
cells and rat2 cells engineered to express RasGRP. Protein extracts
were resolved by SDS/PAGE followed by immunoblotting with an antibody
(H176) directed against the amino-terminus of RasGRP.
|
|
Jurkat T cells can be stimulated with antibodies such as OKT3, which
recognizes the extracellular region of the  chain of CD3, a
component of TCR. Treatment with soluble OKT3 activates Ras within 5 minutes in Jurkat T cells. The tyrosine kinase inhibitor herbimycin A
interferes with early T-cell signaling events, including Ras
activation, probably by inhibiting lck and ZAP-70.32 We confirmed that herbimycin A strongly diminished Ras activation (Figure
2). The compound U73122 has been shown to
inhibit PLC-1 and to block the proliferative response in stimulated
T cells.33 We found that U73122 diminished OKT3-stimulated
Ras activation in Jurkat T cells. Inhibition was 2.8-fold when a
saturating concentration of OKT3 was used and 5.3-fold when a
suboptimal concentration of OKT3 was used. The specificity of this
inhibition was demonstrated by showing that the inert analogue U73343
had no effect.
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| Fig 2.
TCR-stimulated Ras activation in Jurkat T cells and the
effects of pharmacologic inhibitors.
Jurkat T cells were preincubated with herbimycin A (protein tyrosine
kinase inhibitor), U73343 (inert analogue) or U73122 (PLC-1
inhibitor), and then stimulated with OKT3 at either a saturating
concentration (10 µg/mL) or at a suboptimal concentration (0.156 µg/mL). Cell lysates were assayed for Ras-GTP using GST-Raf affinity
selection followed by immunoblotting to detect precipitated Ras.
Phospho-Erk and total Ras in lysates were also detected using
immunoblot methods.
|
|
Using subcellular fractionation techniques, RasGRP from untreated cells
was found in both the soluble and particulate fractions. After TCR
stimulation, a reproducible (n = 7) decrease in the relative amount
of soluble RasGRP was detected. In a time-course experiment, this
change in RasGRP fractionation behavior paralleled the activation of
Ras (Figure 3A and 3B).
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| Fig 3.
RasGRP in membranes of activated T cells.
(A) In a time-course experiment, Jurkat T cells were stimulated with
OKT3 for various times and aliquots were assayed for Ras-GTP and total
Ras using immunoblotting methods. (B) Homogenates of Jurkat T cells
from the various time points were separated into particulate (P) and
soluble (S) fractions and RasGRP was immunoblotted with the H176
anti-RasGRP peptide antibody. (C) Membranes from untreated cells, or
from cells treated for 10 minutes with OKT3, were assayed for their
ability to promote transfer of exogenous guanyl nucleotide to
membrane-bound Ras and the sensitivity of this reaction to antibodies
raised against the catalytic domain of RasGRP was determined. Membranes
were preincubated with IgG prepared from immune (I) or preimmune
(pre-I) serum for 12 minutes at 30°C, then
[32P]GTP was added for 1 minute. Ras was
then extracted with detergent and precipitated with an anti-Ras
monoclonal antibody. Coprecipitated, Ras-associated guanyl nucleotides
were resolved by chromatography and quantified. Representative
chromatographic data are shown. The graphed values are the average of
triplicate assays. Values were normalized to the value obtained when
full association was achieved by incubation with EDTA, followed by
addition of excess MgCl2 to stabilize the Ras-guanyl
nucleotide complex before immune-precipitation. (D) In vitro Ras guanyl
nucleotide exchange reactions were performed with recombinant Sos and
RasGRP in the presence of IgG to demonstrate the specificity of the J32
antibodies.
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Stimulation of Jurkat T cells with OKT3 also resulted in a prompt
5.9-fold increase in the ability of subsequently isolated membranes to
support the transfer of [32P]GTP to
endogenous, membrane-bound Ras (Figure 3C). In both the stimulated and
untreated membranes, much of this newly associated guanyl nucleotide
was converted to GDP during the course of the reaction, a phenomenon
that we attribute to the presence of Ras GAPs in these membrane
preparations. Ras is constitutively associated with the plasma membrane
and we found TCR stimulation does not affect the amount of Ras in
T-cell membrane preparations (data not shown). Significantly, we found
that stimulated labeling of Ras could be blocked by adding purified
antibodies (J32) directed against RasGRP catalytic domain (Figure 3C).
In control experiments with purified proteins in vitro, we demonstrated
that J32 antibodies specifically inhibit the Ras GEF activity of
recombinant RasGRP but not that of Sos (Figure 3D).
To assess the effects of excess RasGRP on TCR signaling, Jurkat T cells
were engineered to overexpress the human RasGRP cDNA using a bovine
papilloma-based vector with an inducible promoter (Figure
4A). Overexpression of RasGRP resulted in
higher OKT3-induced levels of Ras-GTP and Ras activation was relatively
sustained, compared to the case with normal RasGRP levels (Figure 4B).
Overexpression also modestly enhanced acute activation of Ras by PMA.
The level of phospho-Erk closely paralleled the level of Ras-GTP in
this experiment. In a separate experiment, we examined the effects of
RasGRP overexpression on the level of Erk phosphorylation achieved at
various concentrations of OKT3. RasGRP overexpression increased the
absolute amount of phosphorylated Erk observed at a saturating concentration of stimulating antibody and it decreased the
concentration of OKT3 required to elicit a given level of Erk
phosphorylation (Figure 4C).
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| Fig 4.
TCR-Ras-Erk signaling and agonist-induced IL-2 secretion
in Jurkat T cells overexpressing RasGRP.
(A) Jurkat cells transformed with either the empty vector pBMGNeo (Neo)
or the same vector containing full-length human RasGRP (GRP) were
induced with 5.0 µmol/L CdCl2 for 24 hours, as indicated,
then examined for RasGRP expression by immunoblotting using the H176
antibody. (B) Cells expressing BMGNeo or RasGRP were induced with
CdCl2 for 24 hours then stimulated with either 50 ng/mL PMA
for 10 minutes or 0.156 µg/mL OKT3 for various periods. Cells were
then harvested, lysed, and assayed for Ras-GTP, phospho-Erk and total
Erk. (C) Cells from the same cultures as in (A) were stimulated with
various concentrations of OKT3 for 15 minutes at 37°C and then
directly lysed in SDS sample buffer. The lysates were then probed for
phospho-Erk. The bands representing phospho-Erk were quantified by
densitometry and plotted versus the concentration of OKT3. Samples were
also probed with an anti-Erk antibody to verify that similar amounts of
total Erk protein were present (data not shown). (D) Cells were induced
with CdCl2 as indicated for 24 hours then stimulated for 48 hours with the calcium ionophore A23187 (A, 0.5 µmol/L) and either
PMA (24 nmol/L) or bryostatin-1 (Bryo, 10 nmol/L). IL-2 in the medium
was then measured. Values are the average of quadruplicate samples,
with the standard error of the mean indicated.
|
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Although TCR signaling can lead to IL-2 synthesis and secretion in a
normal T-cell response, Jurkat T cells do not synthesize IL-2 after
treatment with soluble OKT3. Conventionally, a calcium ionophore and a
DAG analogue such as PMA, which are thought to activate calcineurin and
PKC, respectively, are used to stimulate IL-2 in Jurkat T cells. We
found that RasGRP overexpressing Jurkat T cells produced substantially
more IL-2 than the control cells on dual stimulation (Figure 4D). This
effect was also seen with the combination of calcium ionophore and
bryostatin-1, a heterocyclic lactone that also acts as a DAG
analogue.34-37 Note that for each DAG analogue, the levels
of IL-2 measured roughly correlate with the levels of RasGRP expressed
in these cells (Figure 4A). Negligible IL-2 was detected in the medium
when no agonist or only 1 agonist was used (data not shown).
| |
Discussion |
The presence of RasGRP in T cells leads to the hypothesis that it
positively regulates Ras during TCR signaling. This hypothesis is
supported by the following observations: (1) TCR-induced Ras activation
is diminished by a PLC-1 inhibitor, (2) RasGRP is differentially
associated with membranes after TCR stimulation, (3) the increased Ras
guanyl nucleotide association activity in membranes from TCR-stimulated
cells is inhibited by anti-RasGRP antibodies, and (4) Jurkat T cells
that overexpress RasGRP are hypersensitive to TCR-Ras-Erk signaling and
hypersensitive to agonist-induced IL-2 secretion. These studies support
a model of T-cell signaling whereby receptor stimulation leads to
activation of PLC-1 followed by the generation of membrane DAG,
RasGRP membrane recruitment, and Ras activation. Our model may help
explain several puzzling facts about TCR signaling including the
observation that stimulation of PLC-1 by ectopically expressed
G-protein-coupled receptors leads to T-cell activation.38
One could propose that PLC-1-generated free cytoplasmic calcium
regulates RasGRP through its EF hands. However, we observed that RasGRP
can activate Ras in vivo even in the presence of EGTA plus BAPTA/AM,
compounds that sequester extracellular and intracellular calcium,
respectively (data not shown).
Diacylglycerol is known to activate PKC and independent evidence
indicates that PKC function is required for TCR
signaling.39 Indeed, PMA-stimulated PKC probably activates
phospholipase D, which can indirectly generate DAG at later stages of T
cell activation.40 Regardless of this complexity, the
demonstration here that DAG analogues can also directly activate RasGRP
and thereby promote Ras signaling in T cells is exciting. Bryostatins
activate PKC, have potent growth inhibitory effects on certain cell
types, and are currently being tested in clinical trials as
antineoplastic agents.41 Like PMA, however, bryostatin-1
also activates Ras in Jurkat T cells and in rat2 cells that ectopically
express RasGRP (Stang and Stone, unpublished data). Furthermore, in
this latter situation, bryostatin-1 activates Ras-Erk by a mechanism
that depends on the DAG-binding domain of RasGRP. Taken together, our results suggest that DAG analogues could be exploited to regulate RasGRP and thereby modulate the immune response.
It should be noted that Ras-Erk signaling is thought to play important
roles at a number of stages in the life of a T cell. Early growth and
maturation in the thymus are dependent on a pre-TCR complex42 and on Ras-Erk signaling.43,44 After
T-cell maturation, autocrine and paracrine action of IL-2 is thought to
contribute to Ras activation.45,46 RasGRP could facilitate
Ras activation during these stages, as well.
Our findings do not address the role of Sos in TCR signaling, nor do
they preclude a role for PKC down-regulation of Ras GAPs. Multiple
forms of Ras regulation might allow a common Ras switch to
differentially respond to diverse external stimuli and developmental cues, and thereby orchestrate distinct biochemical changes and biologic
responses. For example, the amplitude or duration of Ras signaling
might be varied according to the combination of regulatory mechanisms deployed.
| |
Acknowledgments |
We thank Gideon Bollag for recombinant Sos, Ed Chan for useful
suggestions, and Nancy Dower for careful reading of the manuscript.
| |
Footnotes |
Submitted November 10, 1999; accepted January 21, 2000.
Supported by grants to J.C.S., H.L.O., and R.C.B. from the Medical
Research Council and the National Cancer Institute of Canada.
Reprints: James C. Stone, Department of Biochemistry,
University of Alberta, Edmonton, Alberta, Canada T6G 2H7; e-mail jim.stone{at}ualberta.ca.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction