|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 275, Issue 20, 14838-14845, May 19, 2000
From the We investigated whether microtubule-interfering
agents (MIAs: taxol, colchicine, nocodazole, vinblastine, vincristine,
17- Two isoforms of cyclooxygenase
(COX),1 designated COX-1 and
COX-2 catalyze the synthesis of prostaglandins (PGs) from arachidonic acid. COX-1 is constitutively expressed in most tissues and appears to
be responsible for various physiological functions (1, 2). In contrast,
COX-2 is not detectable in most normal tissues but is induced by
oncogenes, growth factors, cytokines, and tumor promoters (3-9).
COX-2 is an important target for treating arthritis, pain, and possibly
cancer (10-12). For example, the expression of COX-2 is increased in
inflamed tissues such as rheumatoid synovium (13), and selective COX-2
inhibitors are useful for the treatment of arthritis (11). COX-2 is
also overexpressed in transformed cells (8, 14, 15) and in tumors
(16-19). Mice engineered to be COX-2-deficient are protected against
developing intestinal tumors (20) and skin papillomas (21).
Additionally, selective COX-2 inhibitors prevent the formation of
intestinal (20, 22) and skin tumors (23) in experimental animals and
suppress the growth of transplantable tumors (24, 25). With this in
mind, it is reasonable to postulate that compounds that induce COX-2
could predispose to cancer or inflammation.
Microtubule-interfering agents (MIAs) are widely used for the treatment
of cancer. The anti-cancer properties of MIAs have been attributed in
part to interference with microtubule assembly, impairment of mitosis,
and changes in cytoskeleton (26). There is growing evidence, however,
that MIAs have multiple cellular effects. For example, MIAs stimulate
mitogen-activated protein kinases (MAPKs) and gene expression (27-29).
Taxol, a novel anti-cancer drug and MIA, up-regulates COX-2 and
synthesis of PGE2 (30, 31). Colchicine and vinblastine, two
other MIAs, stimulate PGE2 production (32, 33). These
findings raise the possibility that COX-2 is a downstream target of
MIAs and possibly other compounds that affect the cytoskeleton.
In this study, we show that MIAs stimulate the expression of the
COX-2 gene in human mammary epithelial cells. These effects were mediated via extracellular-regulated kinases (ERK1/2) and p38
MAPKs. Possibly, MIA-mediated induction of COX-2 will decrease the
efficacy of these compounds as anti-cancer agents or explain, in part,
the toxicity of these drugs.
Materials--
Minimum Eagle's medium and LipofectAMINE were
from Life Technologies, Inc. Keratinocyte basal medium (KBM) was from
Clonetics Corp. (San Diego, CA). Sodium arachidonate, epidermal growth
factor, 17- Tissue Culture--
The 184B5/HER cell line has been described
previously (34). Cells were maintained in minimum Eagle's medium-KBM
mixed in a ratio of 1:1 (basal medium) containing epidermal growth
factor (10 ng/ml), hydrocortisone (0.5 µg/ml), transferrin (10 µg/ml), gentamicin (5 µg/ml), and insulin (10 µg/ml) (growth
medium). Cells were grown to 60% confluence, trypsinized with 0.05%
trypsin-2 mM EDTA, and plated for experimental use. In all
experiments, 184B5/HER cells were grown in basal medium for 24 h
before treatment. Treatments with vehicle (0.1% Me2SO) or
MIAs were always carried out in basal medium.
PGE2 Production--
5 × 104
cells/well were plated in 6-well dishes and grown to 60% confluence in
growth medium. Levels of PGE2 released by the cells were
measured by enzyme immunoassay (8). Production of PGE2 was
normalized to protein concentrations.
Western Blotting--
Cell lysates were prepared by treating
cells with lysis buffer (150 mM NaCl, 100 mM
Tris (pH 8.0), 1% Tween 20, 50 mM diethyldithiocarbamate, 1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride,
10 µg/ml aprotinin, 10 µg/ml trypsin inhibitor, and 10 µg/ml
leupeptin). Lysates were sonicated for 20 s on ice and centrifuged
at 10,000 × g for 10 min to sediment the particulate
material. The protein concentration of the supernatant was measured by
the method of Lowry et al. (35). SDS-polyacrylamide gel
electrophoresis was performed under reducing conditions on 10%
polyacrylamide gels as described by Laemmli (36). The resolved proteins
were transferred onto nitrocellulose sheets as detailed by Towbin
et al. (37). The nitrocellulose membrane was then incubated
with primary antisera. Secondary antibody to IgG conjugated to
horseradish peroxidase was used. The blots were probed with the ECL
Western blot detection system according to the manufacturer's instructions.
Northern Blotting--
Total cellular RNA was isolated from cell
monolayers using an RNA isolation kit from Qiagen Inc. 10 µg of total
cellular RNA per lane were electrophoresed in a formaldehyde-containing
1.2% agarose gel and transferred to nylon-supported membranes. After baking, membranes were prehybridized overnight in a solution containing 50% formamide, 5× sodium chloride/sodium phosphate/EDTA buffer (SSPE), 5× Denhardt's solution, 0.1% SDS, and 100 µg/ml
single-stranded salmon sperm DNA and then hybridized for 12 h at
42 °C with radiolabeled cDNA probes for human COX-2
cDNA and 18 S rRNA. After hybridization, membranes were washed
twice for 20 min at room temperature in 2× SSPE, 0.1% SDS, twice for
20 min in the same solution at 55 °C, and twice for 20 min in 0.1×
SSPE, 0.1% SDS at 55 °C. Washed membranes were then subjected to
autoradiography. COX-2 and 18 S rRNA probes were labeled
with [32P]CTP by random priming.
Nuclear Run-off Assay--
2.5 × 105 cells
were plated in four T150 dishes for each condition. Cells were grown in
growth medium until approximately 60% confluent. Nuclei were isolated
and stored in liquid nitrogen. For the transcription assay, nuclei
(1.0 × 107) were thawed and incubated in reaction
buffer (10 mM Tris (pH 8), 5 mM
MgCl2, and 0.3 M KCl) containing 100 µCi of
uridine 5'-[32P]triphosphate and 1 mM
unlabeled nucleotides. After 30 min, labeled nascent RNA transcripts
were isolated. The human COX-2 and 18 S rRNA cDNAs were
immobilized onto nitrocellulose and prehybridized overnight in
hybridization buffer. Hybridization was carried out at 42 °C for
24 h using equal cpm/ml labeled nascent RNA transcripts for each
treatment group. The membranes were washed twice with 2× SSC (buffer
for 1 h at 55 °C and then treated with 10 mg/ml RNase A in 2×
SSC at 37 °C for 30 min, dried, and autoradiographed.
Plasmids--
The COX-2 promoter constructs
( Oligonucleotides--
CRE-decoy and control oligonucleotides
were phosphorothioate oligonucleotides. Their sequences were as
follows: 24-mer CRE palindrome, 5'-TGACGTCATGACGTCATGACGTCA-3'; 24-mer
CRE mismatch control, 5'-TGTGGTCATGTGGTCATGTGGTCA-3'; and 24-mer
mutant-sequence palindrome, 5'-CTAGCTAGCTAGCTAGCTAGCTAG-3'. In
addition, the following oligonucleotides containing the CRE of the
COX-2 promoter were synthesized:
5'-AAACAGTCATTTCGTCACATGGGCTTG-3' (sense),
5'-CAAGCCCATGTGACGAAATGACTGTTT-3' (antisense). These
oligonucleotides were synthesized by Genosys Biotechnologies, Inc. (The
Woodlands, TX).
Transient Transfection Assays--
184B5/HER cells were seeded
at a density of 5 × 104 cells/well in 6-well dishes
and grown to 50-60% confluence. For each well, 2 µg of plasmid DNA
were introduced into cells using 8 µg of LipofectAMINE as per the
manufacturer's instructions. After 7 h of incubation, the medium
was replaced with basal medium. The activities of luciferase and
Statistics--
Comparisons between groups were made by the
Student's t test. A difference between groups of
p < 0.05 was considered significant.
Microtubule-interfering Agents Induce COX-2--
The possibility
that MIAs could stimulate PG synthesis was investigated in 184B5/HER
human mammary epithelial cells. This HER-2/neu-overexpressing mammary
epithelial cell line was used because MIAs such as taxol are used to
treat women with HER-2/neu-positive breast cancer. The data in Fig.
1 show that taxol, vinblastine, and
colchicine caused dose-dependent increases in
PGE2 production. Nocodazole, vincristine, and
2-methoxyestradiol also stimulated PG synthesis (data not shown). To
determine whether these changes in PGE2 synthesis were
related to differences in amounts of COX-2, Western blotting of cell
lysate protein was carried out. Fig. 2
shows that multiple MIAs including taxol, colchicine, and vincristine induced COX-2 protein. In contrast, COX-2 was not induced by
10-deacetylbaccatin III and
To further elucidate the mechanism responsible for MIA-mediated
induction of COX-2, we determined steady-state levels of COX-2 mRNA
by Northern blotting (Fig. 3). Treatment
with MIAs markedly increased amounts of COX-2 mRNA. Nuclear
run-offs were performed to determine if MIAs stimulated
COX-2 transcription. As shown in Fig.
4, higher rates of synthesis of nascent
COX-2 mRNA were detected after treatment with MIAs (taxol,
colchicine).
Defining the Signaling Mechanism by Which Microtubule-interfering
Agents Induce COX-2 Expression--
Rho is important for regulating
both the cytoskeleton and COX-2. Hence, we determined whether a
dominant negative form of Rho blocked MIA-mediated stimulation of
COX-2 promoter activity. Taxol-mediated induction of
COX-2 promoter activity was blocked by DN Rho (Fig.
5). Similar effects were observed with
other MIAs (data not shown). By contrast, DN Ras did not inhibit
MIA-mediated stimulation of COX-2 promoter activity (data
not shown). Rho can activate protein kinase C, a known regulator of
COX-2 transcription (40). Therefore, we determined whether calphostin
C, an inhibitor of protein kinase C, could block MIA-mediated induction
of COX-2. Calphostin C inhibited the induction of COX-2 protein by
taxol (Fig. 6A) and colchicine
(Fig. 6B).
Protein kinase C can activate Raf-1 which, in turn, regulates MAPK
kinase activity (41). To determine the role of Raf-1 in mediating the
effects of MIAs on COX-2, transient transfections were performed. As
shown in Fig. 6C, MIA-mediated stimulation of
COX-2 promoter activity was blocked by kinase-deficient
Raf-1. Additionally, MIAs have been reported to induce MAPK activity. Treatment with MIAs activated ERK1/2, p38, and JNK MAPKs (Fig. 7). Subsequently, experiments were done
to demonstrate that MIA-mediated increases in MAPK activity were linked
to the induction of COX-2. In the first experiment, we utilized PD
98059, a specific inhibitor of MAPK kinase activity that prevents
activation of ERK1 and ERK2 (42). PD 98059 inhibited the induction of
COX-2 by MIAs (Fig. 8). Similarly, SB
202190, a selective inhibitor of p38 MAPK activity (43), blocked
MIA-mediated induction of COX-2 protein (Fig. 8). To further
investigate the importance of MAPKs in mediating the effects of MIAs, a
series of transient transfections was performed (Fig. 8C).
The induction of COX-2 promoter activity by taxol was blocked by transiently overexpressing dominant negatives for ERK1 or
p38 MAPK. Similar results were obtained with colchicine (data not
shown).
The Cyclic AMP Response Element and AP-1 Mediate the Induction of
COX-2 by Microtubule-interfering Agents--
Transient transfections
were performed with human COX-2 promoter-luciferase
constructs (Fig. 9A) to
identify the region of the COX-2 promoter that was
responsible for MIA-mediated induction of COX-2. Treatment with MIAs
(10 µM) led to about a 3-fold increase in
COX-2 promoter (
Electrophoretic mobility shift assays were performed to identify the
transcription factor that mediated the induction of COX-2 by MIAs. MIAs
caused increased binding to the CRE site of the COX-2
promoter (Fig. 10B). The DNA binding complex induced by
taxol was removed with antibodies to c-Jun, ATF-2 (Fig. 10B)
or c-Fos (Fig. 10C). In contrast, antibodies to NF Cytochalasin D, an Inhibitor of Actin Polymerization, Stimulates
COX-2 Transcription--
The induction of COX-2 by MIAs could be
mediated by effects on the cytoskeleton. Hence, we also determined
whether cytochalasin D, an inhibitor of actin polymerization, induced
COX-2. Cytochalasin D induced COX-2 protein (Fig. 2F) and
COX-2 mRNA (Fig. 3E) by stimulating COX-2
transcription (Fig. 4). These inductive effects were blocked by
calphostin C (data not shown). Treatment with cytochalasin D increased
the activity of ERK1/2 and p38 MAPK (Fig. 7). Furthermore, dominant
negative forms of ERK1 and p38 MAPK blocked cytochalasin D-mediated
activation of the COX-2 promoter (data not shown). Similar
to the MIAs, the inductive effects of cytochalasin D localized to the
CRE of the COX-2 promoter (Fig. 9). Moreover, c-Jun was
important for both cytochalasin D- and MIA-mediated induction of COX-2
promoter activity (Fig. 11).
There is growing evidence that the cytoskeleton is involved in the
propagation of signals that alter gene expression. In addition to the
actin network, cytoplasmic microtubules represent another major element
in the cytoskeleton that have been implicated in intracellular
signaling (26). The current results show that agents that interfere
with microtubules or actin polymerization induce COX-2 gene
expression and PG synthesis in human mammary epithelial cells. Prior
studies have shown that cell transformation and Wnt signaling alter the
cytoskeleton and induce COX-2 (8, 44, 45). Possibly, COX-2 will be
induced by a range of biological processes which affect the cytoskeleton.
Rho GTPases control the organization of the actin cytoskeleton (46).
Additionally, COX-2 can be induced by a Rho-dependent signaling pathway (47). It is noteworthy, therefore, that a dominant
negative form of Rho blocked both MIA- and cytochalasin D-mediated
activation of the COX-2 promoter. As noted above, Rho can
activate protein kinase C (40), which in turn is a known regulator of
COX-2 gene expression (48). The induction of COX-2 by
microtubule- or actin-interfering agents was blocked by calphostin C,
an inhibitor of protein kinase C activity. Although MIAs have been
reported to activate gene expression via the Ras pathway (29), to the
best of our knowledge this is the first time that the protein kinase C
pathway has been implicated. MIAs activate Raf-1 (27), a downstream
target of protein kinase C. The induction of COX-2 promoter
activity by microtubule- or actin-interfering agents was inhibited by
kinase-deficient Raf-1. This is consistent with prior evidence that
COX-2 is a Raf-1-dependent gene (48).
Previously, MIAs were found to induce p38, JNK, and ERK MAPK activities
(27-29, 31). The expression of COX-2 can be affected by changes in
MAPK activity (48-52). Several lines of evidence suggest that MIAs and
cytochalasin D induce COX-2 by activating ERK and p38 MAPKs. Treatment
with MIAs or cytochalasin D stimulated the activities of ERK and p38
MAPK; inhibitors of MAPK kinase and p38 MAPK blocked the induction of
COX-2 by microtubule- or actin-interfering agents. Furthermore,
overexpression of dominant negatives for ERK1 or p38 suppressed the
induction of COX-2 promoter activity by MIAs or cytochalasin
D. Interestingly, the induction of JNK activity by MIAs or cytochalasin
D did not appear to be necessary for induction of COX-2. For example,
taxol-mediated stimulation of COX-2 promoter activity was
not inhibited by a dominant negative form of JNK. This suggests that
phosphorylation of c-Jun is not rate-limiting for MIA-mediated
induction of COX-2. This finding is potentially explained by the
presence of high levels of both unphosphorylated and phosphorylated
c-Jun in 184B5/HER cells under basal conditions.
The AP-1 transcription factor complex consists of a collection of
dimers of members of the Jun, Fos, and ATF/cAMP-response element-binding protein bZip families. MAPKs regulate AP-1 activity by
both increasing the abundance of AP-1 components and stimulating their
activity (53). ERK1/2 MAPK regulates the transcription of c-Fos. p38
MAPK phosphorylates and activates ATF-2 (53). The current results
suggest that the AP-1 transcription factor complex mediates the
induction of COX-2 by microtubule- or actin-interfering agents.
Treatment with MIAs or cytochalasin D augmented binding to the CRE of
the COX-2 promoter (Fig. 10); c-Jun, c-Fos, and ATF-2 were
identified in the DNA binding complex. The functional importance of
AP-1 was established because MIA- or cytochalasin D-mediated induction
of COX-2 promoter activity was suppressed by dominant negative c-Jun (Fig. 11B). This finding is consistent with
previous reports that MIAs can stimulate AP-1 activity (29). The
results are also consistent with the findings of Xie and Herschman (49, 50), who showed that, in response to expression of v-src or treatment with platelet-derived growth factor, c-Jun induced murine Cox-2 via the CRE site. Tumor-promoting phorbol esters, transforming growth factor Pharmacologic concentrations of estrogen inhibit cell proliferation in
estrogen receptor-positive and -negative human breast cancer cell lines
(39). This effect has been attributed to estradiol-induced microtubule
disruption (39, 55). Hence, it was relevant to determine whether
17 The products of COX-2 activity, i.e. PGs, stimulate cell
proliferation (57), inhibit immune surveillance (58), increase the
invasiveness of malignant cells (59), and enhance the production of
vascular endothelial growth factor (60). Possibly, MIA-mediated induction of COX-2 will decrease the efficacy of taxol, vincristine, or
vinblastine as anti-cancer agents. It will be worthwhile, therefore, to
evaluate whether the addition of a selective COX-2 inhibitor can
increase the antitumor activity of MIAs such as taxol. COX-2-derived PGs also contribute to inflammation and pain (11). Taxol has been
reported to cause arthralgias and myalgias in up to 75% of patients
(61, 62). The symptoms of joint and muscle discomfort may last for 3-5
days following completion of taxol therapy. The results of this study
raise the possibility that the toxicity (e.g. myalgias,
arthralgias) of drugs such as taxol could be mediated in part by
COX-2-derived PGs. Additional studies are warranted to determine
whether COX-2 inhibitors can decrease the side effects of MIAs.
*
This work was supported in part by S/G 2P01 CA68425 and the
James E. Olson Memorial Fund.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§
To whom correspondence should be addressed: New York Presbyterian
Hospital-Cornell, Div. of Gastroenterology and Hepatology, Rm. F-203,
1300 York Ave., New York, NY 10021. Tel.: 212-746-4402; Fax:
212-746-4885; E-mail: ksubba@mail.med.cornell.edu.
The abbreviations used are:
COX, cyclooxygenase;
AP-1, activator protein-1;
CRE, cyclic AMP response element;
DN, dominant negative;
ERK, extracellular signal-regulated kinase;
JNK, c-Jun N-terminal kinase;
KBM, keratinocyte basal medium;
MAPK, mitogen-activated protein kinase;
MIA, microtubule-interfering agent;
PGs, prostaglandins;
PGE2, prostaglandin
E2.
Microtubule-interfering Agents Stimulate the Transcription of
Cyclooxygenase-2
EVIDENCE FOR INVOLVEMENT OF ERK1/2 AND p38 MITOGEN-ACTIVATED
PROTEIN KINASE PATHWAYS*
§,,
Department of Medicine, New York
Presbyterian Hospital-Cornell and Strang Cancer Prevention Center and
¶ Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer
Center, New York, New York 10021
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-estradiol, 2-methoxyestradiol) altered cyclooxygenase-2 (COX-2)
expression in human mammary epithelial cells. MIAs enhanced
prostaglandin E2 synthesis and increased levels of
COX-2 protein and mRNA. Nuclear run-off assays revealed increased
rates of COX-2 transcription after treatment with MIAs.
Calphostin C, an inhibitor of protein kinase C, blocked the induction
of COX-2 by MIAs. The stimulation of COX-2 promoter
activity by MIAs was inhibited by overexpressing dominant negative
forms of Rho and Raf-1. MIAs stimulated ERK, JNK, and p38
mitogen-activated protein kinases (MAPK); pharmacological inhibitors of
MAPK kinase and p38 MAPK blocked the induction of COX-2 by MIAs.
Overexpressing dominant negative forms of ERK1 or p38 MAPK inhibited
MIA-mediated activation of the COX-2 promoter. MIAs
stimulated the binding of the activator protein-1 transcription factor
complex to the cyclic AMP response element in the COX-2 promoter. A dominant negative form of c-Jun inhibited the activation of
the COX-2 promoter by MIAs. Additionally, cytochalasin D,
an agent that inhibits actin polymerization, stimulated
COX-2 transcription by the same signaling pathway as MIAs.
Thus, microtubule- or actin-interfering agents stimulated MAPK
signaling and activator protein-1 activity. This led, in turn, to
induction of COX-2 gene expression via the cyclic AMP
response element site in the COX-2 promoter.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-estradiol, 2-methoxyestradiol, hydrocortisone, and
o-nitrophenyl--D-galactopyranoside were from
Sigma. Calphostin C, taxol, colchicine, nocodazole, vinblastine,
vincristine, and cytochalasin D were from Biomol Research Laboratories,
Inc. (Plymouth Meeting, PA). PD 98059 (2'-amino-3'-methoxyflavone) and
SB 202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole) were
from Calbiochem. Enzyme immunoassay reagents for PGE2
assays were from Cayman Co. (Ann Arbor, MI). [32P]ATP,
[32P]CTP, and [32P]UTP were from NEN Life
Science Products. Random-priming kits were from Roche Molecular
Biochemicals. Nitrocellulose membranes were from Schleicher & Schuell.
Reagents for the luciferase assay were from Analytical Luminescence
(San Diego, CA). The 18 S rRNA cDNA was from Ambion, Inc. (Austin,
TX). Goat polyclonal anti-human COX-2 was from Santa Cruz
Biotechnology, Inc. (Santa Cruz, CA). Antibodies to phosphosphorylated
forms of ERK1/2, c-Jun, and p38 were from New England Biolabs Inc.
(Beverly, MA). Western blotting detection reagents (ECL) were from
Amersham Pharmacia Biotech. Plasmid DNA was prepared using a kit
from Promega Corp. (Madison, WI).
1432/+59, 327/+59, 220/+59, 124/+59, 52/+59, KBM, ILM, CRM)
were a generous gift of Dr. Tadashi Tanabe (National Cardiovascular
Center Research Institute, Osaka, Japan) (6). The human
COX-2 cDNA was generously provided by Dr. Stephen M. Prescott (University of Utah, Salt Lake City, UT). The dominant
negative (DN) expression vector for Rho was a gift of Dr. Alan Hall
(University College, London, UK). The expression vector for
kinase-deficient Raf-1 was obtained from Dr. Ulf Rapp (University of
Wurzburg, Germany). The ERK1 DN expression vector was obtained from Dr.
Melanie Cobb (Southwestern Medical Center, Dallas, TX). The DN
expression vectors for JNK and p38 were generously provided by Dr.
Roger Davis (University of Massachusetts, Worcester, MA). A c-Jun DN
expression vector was a gift of Dr. Tom Curran (St. Jude Children's
Research Hospital, Memphis, TN). pSV-gal was obtained from Promega Corp.
-galactosidase were measured in cellular extract as described previously (38).
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-lumicolchicine, structural analogues of
taxol and colchicine that do not interfere with microtubules (data not
shown). Because of evidence (39) that estrogen and its derivatives
interfere with microtubules, the effects of 17-estradiol and
2-methoxyestradiol were determined. Treatment with 17-estradiol or
2-methoxyestradiol induced COX-2 protein (Figs. 2, D and
E). COX-2 was up-regulated at concentrations as low as 25 nM 2-methoxyestradiol (Fig. 2E). The extent of
MIA-mediated induction of COX-2 was comparable with that observed
following treatment with PMA (data not shown).
View larger version (16K):
[in a new window]
Fig. 1.
PGE2 production is increased by
treatment with MIAs. 184B5/HER cells were treated with 0-10
µM taxol (A), vinblastine (B), or
colchicine (C) for 4.5 h. The medium was then replaced
with fresh medium containing 10 µM sodium arachidonate.
30 min later, the medium was collected to determine the synthesis of
PGE2. Production of PGE2 was determined by
enzyme immunoassay. Columns, means; bars, S.D.;
n = 6. *, p < 0.01 compared with
untreated cells.
View larger version (32K):
[in a new window]
Fig. 2.
COX-2 protein is induced by MIAs or
cytochalasin D. Cells were treated with MIAs or cytochalasin D for
4.5 h. Cellular lysate protein (25 µg/lane) was
loaded onto a 10% SDS-polyacrylamide gel, electrophoresed, and
subsequently transferred onto nitrocellulose. Immunoblots were probed
with antibody specific for COX-2. A, lysate protein was from
cells treated with vehicle (lane 1) or taxol (0.01, 0.1, 1, 5, 10 µM; lanes 2-6). B, lysate
protein was from cells treated with vehicle (lane 1) or
colchicine (1, 5, 10 µM; lanes 2-4).
C, lysate protein was from cells treated with vehicle
(lane 1) or vincristine (0.01, 0.1, 1, 10 µM;
lanes 2-5). D, lysate protein was from cells
treated with vehicle (lane 1) or 17- -estradiol (0.5, 1, 5, 10 µM; lanes 2-5). E, lysate
protein was from cells treated with vehicle (lane 1) or
2-methoxyestradiol (0.025, 0.050, 0.1, 1, 5 µM;
lanes 2-6). F, lysate protein was from cells treated with
vehicle (lane 1) or cytochalasin D (1, 5, 10 µM; lanes 2-4).
View larger version (23K):
[in a new window]
Fig. 3.
Microtubule- or actin-interfering agents
induce COX-2 mRNA. Total RNA was isolated from cells that were
treated with MIAs for 3 h. In each panel, lane
1 represents vehicle. Lanes 2-5 represent 1, 2.5, 5, and 10 µM taxol (A), colchicine
(B), vinblastine (C), nocodazole (D),
and cytochalasin D (E). 10 µg of RNA was added to each
lane. Blots were hybridized with probes that recognized
COX-2 mRNA and 18 S mRNA.
View larger version (55K):
[in a new window]
Fig. 4.
COX-2 transcription is stimulated by MIAs and
cytochalasin D. Cells were treated with vehicle (lane
1) or 10 µM taxol (lane 2), cytochalasin
D (lane 3), or colchicine (lane 4) for 2 h.
Nuclear run-offs were performed as described under "Experimental
Procedures." The COX-2 and 18 S rRNA cDNAs were immobilized onto
nitrocellulose membranes and hybridized with labeled nascent RNA
transcripts.
View larger version (20K):
[in a new window]
Fig. 5.
Rho is important for MIA-mediated induction
of COX-2. Cells were transfected with 0.9 µg of a human
COX-2 promoter construct ligated to luciferase ( 327/+59)
and 0.2 µg of pSVgal. Bars labeled Rho DN
represent cells that received 0.9 µg of expression vector for
dominant negative Rho. The total amount of DNA in each reaction was
kept constant at 2 µg by using the corresponding empty expression
vectors. Cells were treated with vehicle (Control), 10 µM taxol, or 10 µM cytochalasin D for
8 h. Luciferase activity represents data that have been normalized
to -galactosidase activity. Columns, means;
bars, S.D.; n = 6; *, p < 0.01 compared with taxol or cytochalasin D.
View larger version (24K):
[in a new window]
Fig. 6.
Induction of COX-2 by MIAs is mediated by
protein kinase C and Raf-1. A, cells were treated with
vehicle (lane 1), 10 µM taxol (lane
2), 10 µM taxol plus 1 µM calphostin C
(lane 3), or 10 µM taxol plus 2 µM calphostin C (lane 4) for 4.5 h.
B, cells were treated with vehicle (lane 1), 10 µM colchicine (lane 2), 10 µM
colchicine plus 1 µM calphostin C (lane 3), or
10 µM colchicine plus 2 µM calphostin C
(lane 4). In panels A and B, cellular
lysate protein (25 µg/lane) was loaded onto a 10%
SDS-polyacrylamide gel, electrophoresed, and subsequently transferred
onto nitrocellulose. Immunoblots were probed with antibody specific for
COX-2. C, cells were transfected with 0.9 µg of a human
COX-2 promoter construct ligated to luciferase ( 327/+59)
and 0.2 µg of pSVgal. Bars labeled Raf-1 DN
represent cells that received 0.9 µg of expression vector for
dominant negative Raf-1. The total amount of DNA in each reaction was
kept constant at 2 µg by using corresponding empty expression
vectors. Cells were treated with 10 µM taxol (open
bar), colchicine (black bar), or cytochalasin D
(stippled bar) for 8 h. Luciferase activity represents
data that have been normalized to -galactosidase activity.
Columns, means; bars, S.D.; n = 6; *, p < 0.01 compared with MIA or cytochalasin
D.
View larger version (45K):
[in a new window]
Fig. 7.
Microtubule- or actin-interfering agents
induce the activities of ERK1/2, p38, and JNK MAPK. A,
cells were treated with vehicle (lane 2) or 10 µM colchicine (lane 3), taxol (lane
4), cytochalasin D (lane 5), nocodazole (lane
6) for 10 min. Lane 1, phospho-ERK1/2 standard.
B, cells were treated with vehicle (lane 1) or 10 µM taxol (lane 2), cytochalasin D (lane
3), vinblastine (lane 4), vincristine (lane
5), colchicine (lane 6), nocodazole (lane 7)
for 10 min. Lane 8, phospho-p38 standard. C,
cells were treated with vehicle (lane 2) or 10 µM taxol (lane 3), cytochalasin D (lane
4), colchicine (lane 5), nocodazole (lane
6), vincristine (lane 7) for 15 min. Lane 1,
phospho-c-Jun standard. Cellular protein (100 µg/lane) was
loaded onto a 10% SDS-polyacrylamide gel, electrophoresed, and
subsequently transferred to nitrocellulose. Immunoblots were probed
with antibodies to phosphorylated forms of ERK1/2 (A), p38
(B), and c-Jun (C).
View larger version (40K):
[in a new window]
Fig. 8.
ERK1/2 and p38 MAPKs are important for
MIA-mediated induction of COX-2. A, lysate protein was
from cells treated with vehicle (lane 1), 10 µM taxol (lane 2), 10 µM taxol
with 10 or 20 µM PD 98059 (lanes 3 and
4), 10 µM taxol with 5 or 10 µM
SB 202190 (lanes 5 and 6). B, lysate
protein was from cells treated with vehicle (lanes 1 and
6), colchicine (1 µM, lanes 2 and
7), colchicine (1 µM) with PD 98059 (10, 20, 30 µM, lanes 3-5), or colchicine (1 µM) with SB 202190 (1, 2.5, 5, 10 µM,
lanes 8-11) for 4.5 h. Lane 12 represents
an ovine Cox-2 standard. Cellular lysate protein (25 µg/lane) was loaded onto a 10% SDS-polyacrylamide gel,
electrophoresed, and subsequently transferred onto nitrocellulose.
Immunoblots were probed with an antibody specific for COX-2.
C, cells were transfected with 0.9 µg of a human
COX-2 promoter construct ligated to luciferase ( 327/+59)
and 0.2 µg of pSVgal. Bars labeled ERK1 DN,
JNK DN, p38 DN represent cells that received 0.9 µg of expression vector for ERK1 DN, JNK DN, and p38 DN,
respectively. The total amount of DNA in each reaction was kept
constant at 2 µg by using corresponding empty expression vectors.
Cells were treated with vehicle or taxol (10 µM) for
8 h. Luciferase activity represents data that have been
normalized to -galactosidase activity. Columns, means;
bars, S.D.; n = 6; *, p < 0.01 compared with taxol.
1432/+59) activity. We next attempted to
define the region of the COX-2 promoter that responded to
MIAs. This was accomplished using a series of COX-2 promoter
deletion constructs. As shown in Fig. 9B, basal
COX-2 promoter activity was highest when the 1432/+59
promoter construct was used. As the COX-2 promoter was
shortened, lower basal activities were detected. Thus, the 52/+59
COX-2 promoter construct was about 30% as active as the full-length 1432/+59 COX-2 promoter construct. Treatment
with MIAs markedly induced COX-2 promoter activity with all
promoter-deletion constructs except the 52/+59 promoter construct. A
CRE is present between nucleotides 59 and 53, suggesting that this
element was responsible for mediating the effects of MIAs. To test this idea, transient transfections were performed using COX-2
promoter constructs in which specific enhancer elements including the
CRE were mutagenized. As shown in Fig. 9C, mutagenizing the
CRE site had multiple effects including a decrease in basal promoter
activity and a loss of responsiveness to MIAs. By contrast,
mutagenizing the NF
B and NF-IL-6 sites had little effect on
COX-2 promoter activity. To confirm the importance of the
CRE for mediating the induction of COX-2 by MIAs, a separate series of
transient transfections were performed. We examined the effects of a
CRE-decoy oligonucleotide on MIA-mediated stimulation of
COX-2 promoter activity. The CRE-decoy oligonucleotide
effectively inhibited taxol-mediated activation of the COX-2
promoter (Fig. 10A). In
contrast, neither a CRE mismatch control oligonucleotide nor a
nonsense-sequence palindrome blocked MIA-mediated induction of
COX-2 promoter activity.
View larger version (35K):
[in a new window]
Fig. 9.
Localization of region of COX-2 promoter that
mediates the effects of MIAs and cytochalasin D. A,
schematic of human COX-2 promoter. B, 184B5/HER
cells were transfected with 1.8 µg of a series of human
COX-2 promoter deletion constructs ligated to luciferase
( 1432/+59, 327/+59, 220/+59, 124/+59, 52/+59), and 0.2 µg
pSVgal. C, 184B5/HER cells were transfected with 1.8 µg
of a series of human COX-2 promoter-luciferase constructs
(327/+59; KBM; ILM; CRM) and 0.2 µg pSVgal. KBM represents the
327/+59 COX-2 promoter construct in which the NFB site
was mutagenized; ILM represents the 327/+59 COX-2 promoter
construct in which the NF-IL6 site was mutagenized; CRM refers to the
327/+59 COX-2 promoter construct in which the CRE was
mutagenized. After transfection, cells were treated with vehicle or 10 µM taxol, colchicine, cytochalasin D. Reporter activities
were measured in cellular extract 7 h later. Luciferase activity
represents data that have been normalized with -galactosidase.
Columns, means; bars, SD; n = 6.
View larger version (25K):
[in a new window]
Fig. 10.
Increased binding of c-Jun, c-Fos, and ATF-2
to the CRE of the COX-2 promoter is detected in MIA-treated cells.
A, 184B5 cells were transfected with 0.9 µg of a human
COX-2 promoter construct ligated to luciferase ( 327/+59)
(Control) or COX-2 promoter plus decoy CRE (0.4 µg) or COX-2 promoter plus mismatch CRE (0.4 µg) or
COX-2 promoter plus mutant CRE (0.4 µg). All cells
received 0.2 µg of pSVgal. The total amount of DNA in each
reaction was kept constant at 2 µg by using empty vector. Cells were
treated with 10 µM taxol. Reporter activities were
measured in cellular extract 8 h later. Luciferase activity
represents data that have been normalized with -galactosidase.
Columns, means; bars, S.D.; n = 6. B, in lanes 1-7, 5 µg of nuclear protein
from 184B5/HER cells was incubated with a 32P-labeled
oligonucleotide containing the CRE of COX-2. Lane 1,
vehicle-treated cells; lane 2, cells treated with 10 µM taxol for 30 min; lanes 3 and 4 represent nuclear extract from taxol-treated cells incubated with
antibodies to c-Jun and ATF-2, respectively; lanes 5-7,
cells treated with 10 µM vinblastine, cytochalasin D, and
colchicine for 30 min. C, 5 µg of nuclear protein from
184B5/HER cells was incubated with a 32P-labeled
oligonucleotide containing the CRE of COX-2. Lane 1, cells
treated with 10 µM taxol for 30 min; lanes 2 and 3, nuclear extract from taxol-treated cells incubated
with 1 µl and 2 µl of antibody to c-Fos, respectively. In
B and C, the protein DNA complex that formed was
separated on a 4% polyacrylamide gel.
B p65
or NF-IL6 did not affect binding to the CRE (data not shown). To
further evaluate the importance of AP-1 for mediating the induction of
COX-2 by MIAs, transient transfections were performed. MIAs stimulated AP-1 promoter activity (Fig.
11A). Moreover, a dominant
negative form of c-Jun inhibited the induction of COX-2
promoter activity by MIAs (Fig. 11B). Taken together, these
results indicate that c-Jun is important for mediating the induction of
COX-2 by MIAs.
View larger version (30K):
[in a new window]
Fig. 11.
MIAs and cytochalasin D activate the COX-2
promoter via c-Jun. A, cells were cotransfected with
1.8 µg of the collagenase promoter (which contains an AP-1 site) and
0.2 µg of pSV gal. Twenty-four h after transfection, cells were
treated with 0-10 µM taxol, colchicine, or cytochalasin
D. Reporter activities were measured in cellular extract 8 h
later. B, cells were cotransfected with a human
COX-2 promoter construct ligated to luciferase (327/+59)
and 0.2 µg of pSVgal. Bars labeled c-Jun DN represent
cells that received 0.9 µg of expression vector for c-Jun DN. The
total amount of DNA in each reaction was kept constant at 2 µg by
using corresponding empty expression vectors. Twenty-four h after
transfection, cells were treated with vehicle or 10 µM
taxol, colchicine, or cytochalasin D for 8 h. In panels
A and B, luciferase activity represents data that have
been normalized to -galactosidase activity. Columns,
means; bars, SD. n = 6. *, p < 0.01 compared with compound.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, and ceramide also activate COX-2
transcription via the CRE site in the human COX-2 promoter
(48, 52, 54).
-estradiol or 2-methoxyestradiol, a metabolite of estradiol,
induced COX-2 in transformed human mammary epithelial cells. Both
compounds induced COX-2; COX-2 was induced at concentrations as low as
25 nM 2-methoxyestradiol. Although the physiologic
significance of this finding is uncertain, 30 nM
2-methoxyestrogens has been detected in the serum of pregnant females
(56).
FOOTNOTES
ABBREVIATIONS
REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
1.
Smith, W. L.,
Garavito, R. M.,
and DeWitt, D. L.
(1996)
J. Biol. Chem.
271,
33157-33160 2.
Smith, W. L.,
and DeWitt, D. L.
(1995)
Semin. Nephrol.
15,
179-194[Medline]
[Order article via Infotrieve]
3.
Kujubu, D. A.,
Fletcher, B. S.,
Varnum, B. C.,
Lim, R. W.,
and Herschman, H. R.
(1991)
J. Biol. Chem.
266,
12866-12872 4.
Jones, D. A.,
Carlton, D. P.,
McIntyre, T. M.,
Zimmerman, G. A.,
and Prescott, S. M.
(1993)
J. Biol. Chem.
268,
9049-9054 5.
DuBois, R. N.,
Awad, J.,
Morrow, J.,
Roberts, L. J.,
and Bishop, P. R.
(1994)
J. Clin. Invest.
93,
493-498
6.
Inoue, H.,
Yokoyama, C.,
Hara, S.,
Tone, Y.,
and Tanabe, T.
(1995)
J. Biol. Chem.
270,
24965-24971 7.
Simmons, D. L.,
Levy, D. B.,
Yannoni, Y.,
and Erikson, R. L.
(1989)
Proc. Natl. Acad. Sci. U. S. A.
86,
1178-1182 8.
Subbaramaiah, K.,
Telang, N.,
Ramonetti, J. T.,
Araki, R.,
DeVito, B.,
Weksler, B. B.,
and Dannenberg, A. J.
(1996)
Cancer Res.
56,
4424-4429 9.
Mestre, J. R.,
Subbaramaiah, K.,
Sacks, P. G.,
Schantz, S. P.,
Tanabe, T.,
Inoue, H.,
and Dannenberg, A. J.
(1997)
Cancer Res.
57,
2890-2895 10.
Anderson, G. D.,
Hauser, S. D.,
McGarity, K. L.,
Bremer, M. E.,
Isakson, P. C.,
and Gregory, S. A.
(1996)
J. Clin. Invest.
97,
2672-2679[Medline]
[Order article via Infotrieve]
11.
Lipsky, P. E.,
and Isakson, P. C.
(1997)
J. Rheumatol.
24 (Suppl. 49),
9-14
12.
Dannenberg, A. J.,
and Zakim, D.
(1999)
Semin. Oncol.
26,
499-504[Medline]
[Order article via Infotrieve]
13.
Crofford, L. J.,
Wilder, R. L.,
Ristimaki, A. P.,
Sano, H.,
Remmers, E. F.,
Epps, H. R.,
and Hla, T.
(1994)
J. Clin. Invest.
93,
1095-1101
14.
Kutchera, W.,
Jones, D. A.,
Matsunami, N.,
Groden, J.,
McIntyre, T. M.,
Zimmerman, G. A.,
White, R. L.,
and Prescott, S. M.
(1996)
Proc. Natl. Acad. Sci. U. S. A.
93,
4816-4820 15.
Sheng, G. G.,
Shao, J.,
Sheng, H.,
Hooton, E. B.,
Isakson, P. C.,
Morrow, J. D.,
Coffey, R. J.,
DuBois, R. N.,
and Beauchamp, R. D.
(1997)
Gastroenterology
113,
1883-1891[CrossRef][Medline]
[Order article via Infotrieve]
16.
Kargman, S. L.,
O'Neil, G. P.,
Vickers, P. J.,
Evans, J. F.,
Mancini, J. A.,
and Jothy, S.
(1995)
Cancer Res.
55,
2556-2559 17.
Ristimaki, A.,
Honkanen, N.,
Jankala, H.,
Sipponen, P.,
and Harkonen, M.
(1997)
Cancer Res.
57,
1276-1280 18.
Parett, M. L.,
Harris, R. E.,
Joarder, F. S.,
Ross, M. S.,
Clausen, K. P.,
and Robertson, F. M.
(1997)
Int. J. Oncol.
10,
503-507
19.
Chan, G.,
Boyle, J. O.,
Yang, E. K.,
Zhang, F.,
Sacks, P. G.,
Shah, J. P.,
Edelstein, D.,
Soslow, R. A.,
Koki, A. T.,
Woerner, B. M.,
Masferrer, J. L.,
and Dannenberg, A. J.
(1999)
Cancer Res.
59,
991-994 20.
Oshima, M.,
Dinchuk, J. E.,
Kargman, S. L.,
Oshima, H.,
Hancock, B.,
Kwong, E.,
Trzaskos, J. M.,
Evans, J. F.,
and Taketo, M. M.
(1996)
Cell
87,
803-809[CrossRef][Medline]
[Order article via Infotrieve]
21.
Tiano, H.,
Chulada, P.,
Spalding, J.,
Lee, C.,
Loftin, C.,
Mahler, J.,
Morham, S.,
and Langenbach, R.
(1997)
Proc. Am. Assoc. Cancer Res.
38,
1727 (abstr.)
22.
Kawamori, T.,
Rao, C. V.,
Seibert, K.,
and Reddy, B. S.
(1998)
Cancer Res.
58,
409-412 23.
Fischer, S. M.,
Lo, H-H.,
Gordon, G. B.,
Seibert, K.,
Kelloff, G.,
Lubet, R. A.,
and Conti, C. C.
(1999)
Mol. Carcinog.
25,
231-240[CrossRef][Medline]
[Order article via Infotrieve]
24.
Sheng, H.,
Shao, J.,
Kirkland, S. C.,
Isakson, P.,
Coffey, R. J.,
Morrow, J.,
Beauchamp, R. D.,
and DuBois, R. N.
(1997)
J. Clin. Invest.
99,
2254-2259[Medline]
[Order article via Infotrieve]
25.
Sawaoka, H.,
Kawano, S.,
Tsuji, S.,
Tsujii, M.,
Gunawan, E. S.,
Takei, Y.,
Nagano, K.,
and Hori, M.
(1998)
Am. J. Physiol.
274,
G1061-G1067 26.
Jordan, M. A.,
and Wilson, L.
(1998)
Curr. Opin. Cell Biol.
10,
123-130[CrossRef][Medline]
[Order article via Infotrieve]
27.
Schmid-Alliana, A.,
Menou, L.,
Manie, S.,
Schmid-Antomarchi, H.,
Millet, M-A.,
Giuriato, S.,
Ferrua, B.,
and Rossi, B.
(1998)
J. Biol. Chem.
273,
3394-3400 28.
Lee, L.-F.,
Li, G.,
Templeton, D. J.,
and Ting, J. P.-Y.
(1998)
J. Biol. Chem.
273,
28253-28260 29.
Wang, T.-H.,
Wang, H.-S.,
Ichijo, H.,
Giannakakou, P.,
Foster, J. S.,
Fojo, T.,
and Wimalasena, J.
(1998)
J. Biol. Chem.
273,
4928-4936 30.
Moos, P. J.,
and Fitzpatrick, F. A.
(1998)
Proc. Natl. Acad. Sci. U. S. A.
95,
3896-3901 31.
Moos, P. J.,
Muskardin, D. T.,
and Fitzpatrick, F. A.
(1999)
J. Immunol.
162,
467-473 32.
Gemsa, D.,
Kramer, W.,
Brenner, M.,
Till, G.,
and Resch, K.
(1980)
J. Immunol.
124,
376-380[Abstract]
33.
Yeh, C-K.,
and Rodan, G. A.
(1987)
Biochim. Biophys. Acta
927,
315-323[Medline]
[Order article via Infotrieve]
34.
Zhai, Y-F.,
Beittenmiller, H.,
Wang, B.,
Gould, M. N.,
Oakley, C.,
Esselman, W. J.,
and Welsch, C. W.
(1993)
Cancer Res.
53,
2272-2278 35.
Lowry, O. H.,
Rosebrough, N. J.,
Farr, A. L.,
and Randall, R. J.
(1951)
J. Biol. Chem.
193,
265-275 36.
Laemmli, U. K.
(1970)
Nature
227,
680-685[CrossRef][Medline]
[Order article via Infotrieve]
37.
Towbin, H.,
Staehelin, T.,
and Gordon, J.
(1979)
Proc. Natl. Acad. Sci. U. S. A.
76,
4350-4354 38.
Mestre, J. R.,
Subbaramaiah, K.,
Sacks, P. G.,
Schantz, S. P.,
Tanabe, T.,
Inoue, H.,
and Dannenberg, A. J.
(1997)
Cancer Res.
57,
1081-1085 39.
Aizu-Yokata, E.,
Ichinoseki, K.,
and Sato, Y.
(1994)
Carcinogenesis
15,
1875-1879 40.
Chang, J. H.,
Pratt, J. C.,
Sawasdikosol, S.,
Kapeller, R.,
and Burakoff, S. J.
(1998)
Mol. Cell. Biol.
18,
4986-4993 41.
Reunanen, N.,
Westermarck, J.,
Hakkinen, L.,
Holmstrom, T. H.,
Elo, I.,
Eriksson, J. E.,
and Kahari, V.-M.
(1998)
J. Biol. Chem.
273,
5137-5145 42.
Dudley, D. T.,
Pang, L.,
Decker, S. T.,
Bridges, A. J.,
and Saltiel, A. R.
(1995)
Proc. Natl. Acad. Sci. U. S. A.
92,
7686-7689 43.
Jiang, Y.,
Chen, C.,
Li, Z.,
Guo, W.,
Gegner, J. A.,
Lin, S.,
and Han, J.
(1996)
J. Biol. Chem.
271,
17920-17926 44.
Gunderson, G. G.,
and Cook, T. A.
(1999)
Curr. Opin. Cell Biol.
11,
81-94[CrossRef][Medline]
[Order article via Infotrieve]
45.
Howe, L. R.,
Subbaramaiah, K.,
Chung, W. J.,
Dannenberg, A. J.,
and Brown, A. M. C.
(1999)
Cancer Res.
59,
1572-1577 46.
Mackay, D. J. G.,
and Hall, A.
(1998)
J. Biol. Chem.
273,
20685-20688 47.
Slice, L. W.,
Walsh, J. H.,
and Rozengurt, E.
(1999)
J. Biol. Chem.
274,
27562-27566 48.
Subbaramaiah, K.,
Chung, W. J.,
and Dannenberg, A. J.
(1998)
J. Biol. Chem.
273,
32943-32949 49.
Xie, W.,
and Herschman, H. R.
(1995)
J. Biol. Chem.
270,
27622-27628 50.
Xie, W.,
and Herschman, H. R.
(1996)
J. Biol. Chem.
271,
31742-31748 51.
Guan, Z.,
Buckman, S. Y.,
Pentland, A. P.,
Templeton, D. J.,
and Morrison, A. R.
(1998)
J. Biol. Chem.
273,
12901-12908 52.
Matsuura, H.,
Sakaue, M.,
Subbaramaiah, K.,
Kamitani, H.,
Eling, T. E.,
Dannenberg, A. J.,
Tanabe, T.,
Inoue, H.,
Arata, J.,
and Jetten, A. M.
(1999)
J. Biol. Chem.
274,
29138-29148 53.
Whitmarsh, A. J.,
and Davis, R. J.
(1996)
J. Mol. Med.
74,
589-607[CrossRef][Medline]
[Order article via Infotrieve]
54.
Subbaramaiah, K.,
Chung, W. J.,
Michaluart, P.,
Telang, N.,
Tanabe, T.,
Inoue, H.,
Jang, M.,
Pezzuto, J. M.,
and Dannenberg, A. J.
(1998)
J. Biol. Chem.
273,
21875-21882 55.
D'Amato, R. J.,
Lin, C. M.,
Flynn, E.,
Folkman, J.,
and Hamel, E.
(1994)
Proc. Natl. Acad. Sci. U. S. A.
91,
3964-3968 56.
Berg, D.,
Sonsallla, R.,
and Kuss, E.
(1983)
Acta Endocrinol.
103,
282-288
57.
Sheng, H.,
Shao, J.,
Morrow, J. D.,
Beauchamp, R. D.,
and DuBois, R. N.
(1998)
Cancer Res.
58,
362-366 58.
Goodwin, J. S.,
and Ceuppens, J.
(1983)
J. Clin. Immunol.
3,
295-315[CrossRef][Medline]
[Order article via Infotrieve]
59.
Tsujii, M.,
Kawano, S.,
and DuBois, R. N.
(1997)
Proc. Natl. Acad. Sci. U. S. A.
94,
3336-3340 60.
Tsujii, M.,
Kawano, S.,
Tsuji, S.,
Sawaoka, H.,
Hori, M.,
and DuBois, R. N.
(1998)
Cell
93,
705-716[CrossRef][Medline]
[Order article via Infotrieve]
61.
Holmes, F. A.,
Walters, R. S.,
Theriault, R. L.,
Forman, A. D.,
Newton, L. K.,
Raber, M. N.,
Buzdar, A. U.,
Frye, D. K.,
and Hortobagyi, G. N.
(1991)
J. Natl. Cancer Inst.
83,
1797-1805 62.
Eisenhauer, E. A.,
Huinink, W. W. T. B.,
Swenerton, K. D.,
Gianni, L.,
Myles, J.,
van der Burg, M. E. L.,
Kerr, I.,
Vermorken, J. B.,
Buser, K.,
Colombo, N.,
Bacon, M.,
Santabarbara, P.,
Onetto, N.,
Winograd, B.,
and Canetta, R.
(1994)
J. Clin. Oncol.
12,
1654-2666
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Zhang, L. Qiu, X. Jin, Z. Guo, and C. Guo Nuclear Factor-{kappa}B Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non-Small Cell Lung Cancer In vitro and In vivo Mol. Cancer Res., July 1, 2009; 7(7): 1139 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. R. Healy, F. Zhu, J. D. Stull, and K. Konstantopoulos Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBP{beta}-dependent pathway Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1146 - C1157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Arany, B. K. Wagner, Y. Ma, J. Chinsomboon, D. Laznik, and B. M. Spiegelman Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1{alpha} and oxidative phosphorylation PNAS, March 25, 2008; 105(12): 4721 - 4726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hohla, A. V. Schally, C. A. Kanashiro, S. Buchholz, B. Baker, C. Kannadka, A. Moder, E. Aigner, C. Datz, and G. Halmos Growth inhibition of non-small-cell lung carcinoma by BN/GRP antagonist is linked with suppression of K-Ras, COX-2, and pAkt PNAS, November 20, 2007; 104(47): 18671 - 18676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Mhaidat, R. F. Thorne, X. D. Zhang, and P. Hersey Regulation of Docetaxel-Induced Apoptosis of Human Melanoma Cells by Different Isoforms of Protein Kinase C Mol. Cancer Res., October 1, 2007; 5(10): 1073 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Azim, H. Cao, X. Gao, M. Joo, A. B. Malik, R. B. van Breemen, R. T. Sadikot, G. Park, and J. W. Christman Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L668 - L673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Islam, C. J. Amuzie, J. R. Harkema, and J. J. Pestka Neurotoxicity and Inflammation in the Nasal Airways of Mice Exposed to the Macrocyclic Trichothecene Mycotoxin Roridin A: Kinetics and Potentiation by Bacterial Lipopolysaccharide Coexposure Toxicol. Sci., August 1, 2007; 98(2): 526 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Xu and H.-K. G. Shu EGFR Activation Results in Enhanced Cyclooxygenase-2 Expression through p38 Mitogen-Activated Protein Kinase-Dependent Activation of the Sp1/Sp3 Transcription Factors in Human Gliomas Cancer Res., July 1, 2007; 67(13): 6121 - 6129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yano, T. Matsumura, T. Senokuchi, N. Ishii, Y. Murata, K. Taketa, H. Motoshima, T. Taguchi, K. Sonoda, D. Kukidome, et al. Statins Activate Peroxisome Proliferator-Activated Receptor {gamma} Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase-Dependent Cyclooxygenase-2 Expression in Macrophages Circ. Res., May 25, 2007; 100(10): 1442 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Mhaidat, X. D. Zhang, C. C. Jiang, and P. Hersey Docetaxel-Induced Apoptosis of Human Melanoma Is Mediated by Activation of c-Jun NH2-Terminal Kinase and Inhibited by the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase 1/2 Pathway Clin. Cancer Res., February 15, 2007; 13(4): 1308 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zou, M. Adachi, K. Imai, M. Hareyama, K. Yoshioka, S. Zhao, and Y. Shinomura 2-Methoxyestradiol, an Endogenous Mammalian Metabolite, Radiosensitizes Colon Carcinoma Cells through c-Jun NH2-Terminal Kinase Activation. Clin. Cancer Res., November 1, 2006; 12(21): 6532 - 6539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Csiki and D. H. Johnson Did Targeted Therapy Fail Cyclooxygenase Too? J. Clin. Oncol., October 20, 2006; 24(30): 4798 - 4800. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hirao, N. Tamai, N. Tsumaki, H. Yoshikawa, and A. Myoui Oxygen Tension Regulates Chondrocyte Differentiation and Function during Endochondral Ossification J. Biol. Chem., October 13, 2006; 281(41): 31079 - 31092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Hohla, A. V. Schally, K. Szepeshazi, J. L. Varga, S. Buchholz, F. Koster, E. Heinrich, G. Halmos, F. G. Rick, C. Kannadka, et al. Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel PNAS, September 26, 2006; 103(39): 14513 - 14518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. V. Dantas and K. Sandberg Does 2-Methoxyestradiol Represent the New and Improved Hormone Replacement Therapy for Atherosclerosis? Circ. Res., August 4, 2006; 99(3): 234 - 237. [Full Text] [PDF]
|
|
|
|
|
|
F. Barchiesi, E. K. Jackson, J. Fingerle, D. G. Gillespie, B. Odermatt, and R. K. Dubey 2-Methoxyestradiol, an Estradiol Metabolite, Inhibits Neointima Formation and Smooth Muscle Cell Growth via Double Blockade of the Cell Cycle Circ. Res., August 4, 2006; 99(3): 266 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Tang, A. Shih, H. J. Cao, F. B. Davis, P. J. Davis, and H.-Y. Lin Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Mol. Cancer Ther., August 1, 2006; 5(8): 2034 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Croft and S. A. Przyborski Formation of neurons by non-neural adult stem cells: potential mechanism implicates an artifact of growth in culture. Stem Cells, August 1, 2006; 24(8): 1841 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Wang, C.-Y. Ko, L.-C. Chen, W.-L. Wang, and W.-C. Chang Functional role of NF-IL6{beta} and its sumoylation and acetylation modifications in promoter activation of cyclooxygenase 2 gene Nucleic Acids Res., January 5, 2006; 34(1): 217 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Grishin, J. Wang, D. A. Potoka, D. J. Hackam, J. S. Upperman, P. Boyle, R. Zamora, and H. R. Ford Lipopolysaccharide Induces Cyclooxygenase-2 in Intestinal Epithelium via a Noncanonical p38 MAPK Pathway J. Immunol., January 1, 2006; 176(1): 580 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Csiki, J. D. Morrow, A. Sandler, Y. Shyr, J. Oates, M. K. Williams, T. Dang, D. P. Carbone, and D. H. Johnson Targeting Cyclooxygenase-2 in Recurrent Non-Small Cell Lung Cancer: A Phase II Trial of Celecoxib and Docetaxel Clin. Cancer Res., September 15, 2005; 11(18): 6634 - 6640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, Y. Mao, P. W. Brandt-Rauf, A. C. Williams, and R. L. Fine Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway Mol. Cancer Ther., June 1, 2005; 4(6): 901 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Altorki, J. L. Port, F. Zhang, D. Golijanin, H. T. Thaler, A. J. Duffield-Lillico, K. Subbaramaiah, and A. J. Dannenberg Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non-Small Cell Lung Cancer Clin. Cancer Res., June 1, 2005; 11(11): 4191 - 4197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Daikoku, D. Wang, S. Tranguch, J. D. Morrow, S. Orsulic, R. N. DuBois, and S. K. Dey Cyclooxygenase-1 Is a Potential Target for Prevention and Treatment of Ovarian Epithelial Cancer Cancer Res., May 1, 2005; 65(9): 3735 - 3744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kim, I. A. Murray, A. M. Burns, F. J. Gonzalez, G. H. Perdew, and J. M. Peters Peroxisome Proliferator-activated Receptor-{beta}/{delta} Inhibits Epidermal Cell Proliferation by Down-regulation of Kinase Activity J. Biol. Chem., March 11, 2005; 280(10): 9519 - 9527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Gauthier, C. R. Pickering, C. J. Miller, C. A. Fordyce, K. L. Chew, H. K. Berman, and T. D. Tlsty p38 Regulates Cyclooxygenase-2 in Human Mammary Epithelial Cells and Is Activated in Premalignant Tissue Cancer Res., March 1, 2005; 65(5): 1792 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. W. Yim, H.-S. Jong, T. Y. Kim, H. H. Choi, S. G. Kim, S. H. Song, J. Kim, S.-G. Ko, J. W. Lee, T.-Y. Kim, et al. Cyclooxygenase-2 Inhibits Novel Ginseng Metabolite-Mediated Apoptosis Cancer Res., March 1, 2005; 65(5): 1952 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Bava, V. T. Puliappadamba, A. Deepti, A. Nair, D. Karunagaran, and R. J. Anto Sensitization of Taxol-induced Apoptosis by Curcumin Involves Down-regulation of Nuclear Factor-{kappa}B and the Serine/Threonine Kinase Akt and Is Independent of Tubulin Polymerization J. Biol. Chem., February 25, 2005; 280(8): 6301 - 6308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Qian, K. J. Liu, Y. Chen, D. C. Flynn, V. Castranova, and X. Shi Cdc42 Regulates Arsenic-induced NADPH Oxidase Activation and Cell Migration through Actin Filament Reorganization J. Biol. Chem., February 4, 2005; 280(5): 3875 - 3884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Kim, Y.-H. Kim, K.-J. Shin, Y.-S. Oh, C. S. Lee, K.-O. Kang, S. H. Ryu, and P.-G. Suh 2,2',4,6,6'-Pentachlorobiphenyl-Induced Apoptosis Is Limited by Cyclooxygenase-2 Induction Toxicol. Sci., February 1, 2005; 83(2): 397 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Wang, W.-N. Lin, C.-W. Lee, C.-C. Lin, S.-F. Luo, J.-S. Wang, and C.-M. Yang Involvement of p42/p44 MAPK, p38 MAPK, JNK, and NF-{kappa}B in IL-1{beta}-induced VCAM-1 expression in human tracheal smooth muscle cells Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L227 - L237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zaric and C. Ruegg Integrin-mediated Adhesion and Soluble Ligand Binding Stabilize COX-2 Protein Levels in Endothelial Cells by Inducing Expression and Preventing Degradation J. Biol. Chem., January 14, 2005; 280(2): 1077 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention J. Clin. Oncol., January 10, 2005; 23(2): 254 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun and F. A. Sinicrope Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells Mol. Cancer Ther., January 1, 2005; 4(1): 51 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hinz, R. Ramer, K. Eichele, U. Weinzierl, and K. Brune Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma Cells Mol. Pharmacol., December 1, 2004; 66(6): 1643 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. A. Rossen, J. Bouma, R. H. C. Raatgeep, H. A. Buller, and A. W. C. Einerhand Inhibition of Cyclooxygenase Activity Reduces Rotavirus Infection at a Postbinding Step J. Virol., September 15, 2004; 78(18): 9721 - 9730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Galindo, A. A. Fadl, J. Sha, C. Gutierrez Jr., V. L. Popov, I. Boldogh, B. B. Aggarwal, and A. K. Chopra Aeromonas hydrophila Cytotoxic Enterotoxin Activates Mitogen-activated Protein Kinases and Induces Apoptosis in Murine Macrophages and Human Intestinal Epithelial Cells J. Biol. Chem., September 3, 2004; 279(36): 37597 - 37612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sirois, K. Sayasith, K. A. Brown, A. E. Stock, N. Bouchard, and M. Dore Cyclooxygenase-2 and its role in ovulation: a 2004 account Hum. Reprod. Update, September 1, 2004; 10(5): 373 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Biarc, I. S. Nguyen, A. Pini, F. Gosse, S. Richert, D. Thierse, A. Van Dorsselaer, E. Leize-Wagner, F. Raul, J.-P. Klein, et al. Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis) Carcinogenesis, August 1, 2004; 25(8): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Brown and R. N. DuBois Cyclooxygenase-2 in Lung Carcinogenesis and Chemoprevention: Roger S. Mitchell Lecture Chest, May 1, 2004; 125(5_suppl): 134S - 140S. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Norvell, S. M. Ponik, D. K. Bowen, R. Gerard, and F. M. Pavalko Fluid shear stress induction of COX-2 protein and prostaglandin release in cultured MC3T3-E1 osteoblasts does not require intact microfilaments or microtubules J Appl Physiol, March 1, 2004; 96(3): 957 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Faisal, S. Kleiner, and Y. Nagamine Non-redundant Role of Shc in Erk Activation by Cytoskeletal Reorganization J. Biol. Chem., January 30, 2004; 279(5): 3202 - 3211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Zoubiane, A. Valentijn, E. T. Lowe, N. Akhtar, S. Bagley, A. P. Gilmore, and C. H. Streuli A role for the cytoskeleton in prolactin-dependent mammary epithelial cell differentiation J. Cell Sci., January 15, 2004; 117(2): 271 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. G. Tessner, F. Muhale, S. Schloemann, S. M. Cohn, A. R. Morrison, and W. F. Stenson Ionizing radiation up-regulates cyclooxygenase-2 in I407 cells through p38 mitogen-activated protein kinase Carcinogenesis, January 1, 2004; 25(1): 37 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ott, D. Iwanciw, A. Graness, K. Giehl, and M. Goppelt-Struebe Modulation of the Expression of Connective Tissue Growth Factor by Alterations of the Cytoskeleton J. Biol. Chem., November 7, 2003; 278(45): 44305 - 44311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Kim, S.-G. Hwang, I.-C. Kim, and J.-S. Chun Actin Cytoskeletal Architecture Regulates Nitric Oxide-induced Apoptosis, Dedifferentiation, and Cyclooxygenase-2 Expression in Articular Chondrocytes via Mitogen-activated Protein Kinase and Protein Kinase C Pathways J. Biol. Chem., October 24, 2003; 278(43): 42448 - 42456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. De Lorenzo, K. Yamaguchi, K. Subbaramaiah, and A. J. Dannenberg Bryostatin-1 Stimulates the Transcription of Cyclooxygenase-2: Evidence for an Activator Protein-1-Dependent Mechanism Clin. Cancer Res., October 15, 2003; 9(13): 5036 - 5043. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Castelao, R. D. Bart III, C. A. DiPerna, E. M. Sievers, and R. M. Bremner Lung cancer and cyclooxygenase-2 Ann. Thorac. Surg., October 1, 2003; 76(4): 1327 - 1335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Subbaramaiah, T. P. Marmo, D. A. Dixon, and A. J. Dannenberg Regulation of Cyclooxgenase-2 mRNA Stability by Taxanes: EVIDENCE FOR INVOLVEMENT OF p38, MAPKAPK-2, and HuR J. Biol. Chem., September 26, 2003; 278(39): 37637 - 37647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Dmitrovsky Combining Cytotoxic Chemotherapy With Cyclooxygenase-2 Inhibition J. Clin. Oncol., July 15, 2003; 21(14): 2631 - 2632. [Full Text] [PDF]
|
|
|
|
|
|
N.K. Altorki, R.S. Keresztes, J.L. Port, D.M. Libby, R.J. Korst, D.B. Flieder, C.A. Ferrara, D.F. Yankelevitz, K. Subbaramaiah, M.W. Pasmantier, et al. Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non-Small-Cell Lung Cancer J. Clin. Oncol., July 15, 2003; 21(14): 2645 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Reshkin, A. Bellizzi, R. A. Cardone, M. Tommasino, V. Casavola, and A. Paradiso Paclitaxel Induces Apoptosis via Protein Kinase A- and p38 Mitogen-activated Protein-dependent Inhibition of the Na+/H+ Exchanger (NHE) NHE Isoform 1 in Human Breast Cancer Cells Clin. Cancer Res., June 1, 2003; 9(6): 2366 - 2373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shimada, M. Nakamura, E. Ishida, M. Kishi, and N. Konishi Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis Carcinogenesis, June 1, 2003; 24(6): 1067 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. DuBois Evaluation of the Whole Prostaglandin Biosynthetic Pathway in Lung Cancer Clin. Cancer Res., May 1, 2003; 9(5): 1577 - 1578. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Deacon, P. Mistry, J. Chernoff, J. L. Blank, and R. Patel p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest Mol. Biol. Cell, May 1, 2003; 14(5): 2071 - 2087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chauhan, G. Li, D. Auclair, T. Hideshima, P. Richardson, K. Podar, N. Mitsiades, C. Mitsiades, C. Li, R. S. Kim, et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays Blood, May 1, 2003; 101(9): 3606 - 3614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Giuliano High-Content Profiling of Drug-Drug Interactions: Cellular Targets Involved in the Modulation of Microtubule Drug Action by the Antifungal Ketoconazole J Biomol Screen, April 1, 2003; 8(2): 125 - 135. [Abstract] [PDF]
|
|
|
|
 |
|
 S. A. Milne and H. N. Jabbour Prostaglandin (PG) F2{alpha} Receptor Expression and Signaling in Human Endometrium: Role of PGF2{alpha} in Epithelial Cell Proliferation J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1825 - 1832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Gupta, L. V. Tejada, B. J. Tong, S. K. Das, J. D. Morrow, S. K. Dey, and R. N. DuBois Cyclooxygenase-1 is Overexpressed and Promotes Angiogenic Growth Factor Production in Ovarian Cancer Cancer Res., March 1, 2003; 63(5): 906 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Jung, J. S. Isaacs, S. Lee, J. Trepel, and L. Neckers Microtubule Disruption Utilizes an NFkappa B-dependent Pathway to Stabilize HIF-1alpha Protein J. Biol. Chem., February 21, 2003; 278(9): 7445 - 7452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Tessner, F. Muhale, S. Schloemann, S. M. Cohn, A. Morrison, and W. F. Stenson Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G269 - G279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Yoo, M. P. Piechocki, J. F. Ensley, T. Nguyen, J. Oliver, H. Meng, D. Kewson, T. Y. Shibuya, F. Lonardo, and M. A. Tainsky Docetaxel Induced Gene Expression Patterns in Head and Neck Squamous Cell Carcinoma Using cDNA Microarray and PowerBlot Clin. Cancer Res., December 1, 2002; 8(12): 3910 - 3921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Monick, P. K. Robeff, N. S. Butler, D. M. Flaherty, A. B. Carter, M. W. Peterson, and G. W. Hunninghake Phosphatidylinositol 3-Kinase Activity Negatively Regulates Stability of Cyclooxygenase 2 mRNA J. Biol. Chem., August 30, 2002; 277(36): 32992 - 33000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Han, S. Tsui, and T. J. Smith Up-regulation of Prostaglandin E2 Synthesis by Interleukin-1beta in Human Orbital Fibroblasts Involves Coordinate Induction of Prostaglandin-Endoperoxide H Synthase-2 and Glutathione-dependent Prostaglandin E2 Synthase Expression J. Biol. Chem., May 3, 2002; 277(19): 16355 - 16364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Cassidy, P. J. Moos, R. C. Kelly, and F. A. Fitzpatrick Cyclooxygenase-2 Induction by Paclitaxel, Docetaxel, and Taxane Analogues in Human Monocytes and Murine Macrophages: Structure-Activity Relationships and Their Implications Clin. Cancer Res., March 1, 2002; 8(3): 846 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Samarakoon and P. J. Higgins MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks J. Cell Sci., January 8, 2002; 115(15): 3093 - 3103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Sawyer, S. M. Norvell, S. M. Ponik, and F. M. Pavalko Regulation of PGE2 and PGI2 release from human umbilical vein endothelial cells by actin cytoskeleton Am J Physiol Cell Physiol, September 1, 2001; 281(3): C1038 - C1045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. HALLSWORTH, L. M. MOIR, D. LAI, and S. J. HIRST Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle Am. J. Respir. Crit. Care Med., August 15, 2001; 164(4): 688 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Jorquera and R. M. Tanguay Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability Hum. Mol. Genet., August 1, 2001; 10(17): 1741 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hyun Song, H.-S. Jong, H. H. Choi, H. Inoue, T. Tanabe, N. K. Kim, and Y.-J. Bang Transcriptional Silencing of Cyclooxygenase-2 by Hyper-methylation of the 5' CpG Island in Human Gastric Carcinoma Cells Cancer Res., June 1, 2001; 61(11): 4628 - 4635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Bourgarel-Rey, S. Vallee, O. Rimet, S. Champion, D. Braguer, A. Desobry, C. Briand, and Y. Barra Involvement of Nuclear Factor kappa B in c-Myc Induction by Tubulin Polymerization Inhibitors Mol. Pharmacol., April 16, 2001; 59(5): 1165 - 1170. [Abstract] [Full Text]
|
|
|
|
|
|
V. Subbarayan, A. L. Sabichi, N. Llansa, S. M. Lippman, and D. G. Menter Differential Expression of Cyclooxygenase-2 and Its Regulation by Tumor Necrosis Factor-{{alpha}} in Normal and Malignant Prostate Cells Cancer Res., March 1, 2001; 61(6): 2720 - 2726. [Abstract] [Full Text]
|
|
|
|
|
|
S. Kulkarni, J. S. Rader, F. Zhang, H. Liapis, A. T. Koki, J. L. Masferrer, K. Subbaramaiah, and A. J. Dannenberg Cyclooxygenase-2 Is Overexpressed in Human Cervical Cancer Clin. Cancer Res., February 1, 2001; 7(2): 429 - 434. [Abstract] [Full Text]
|
|
|
|
|
|
K. Subbaramaiah, D. T. Lin, J. C. Hart, and A. J. Dannenberg Peroxisome Proliferator-activated Receptor gamma Ligands Suppress the Transcriptional Activation of Cyclooxygenase-2. EVIDENCE FOR INVOLVEMENT OF ACTIVATOR PROTEIN-1 AND CREB-BINDING PROTEIN/p300 J. Biol. Chem., April 6, 2001; 276(15): 12440 - 12448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-i. Okano and A. K. Rustgi Paclitaxel Induces Prolonged Activation of the Ras/MEK/ERK Pathway Independently of Activating the Programmed Cell Death Machinery J. Biol. Chem., May 25, 2001; 276(22): 19555 - 19564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. de Gregorio, M. A. Iniguez, M. Fresno, and S. Alemany Cot Kinase Induces Cyclooxygenase-2 Expression in T Cells through Activation of the Nuclear Factor of Activated T Cells J. Biol. Chem., July 13, 2001; 276(29): 27003 - 27009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Guzman-Verri, E. Chaves-Olarte, C. von Eichel-Streiber, I. Lopez-Goni, M. Thelestam, S. Arvidson, J.-P. Gorvel, and E. Moreno GTPases of the Rho Subfamily Are Required for Brucella abortus Internalization in Nonprofessional Phagocytes. DIRECT ACTIVATION OF Cdc42 J. Biol. Chem., November 21, 2001; 276(48): 44435 - 44443. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |