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(Received for publication, April 5, 1996, and in revised form, August 5, 1996)
From ABSTRACT The tissue inhibitors of metalloproteinases
(TIMPs) constitute a family of proteins, of which three members have so
far been described. Using the expressed sequence tag sequencing
approach, we have identified a novel TIMP-related cDNA fragment and
subsequently cloned a fourth human TIMP (TIMP-4) from a human heart
cDNA library. The open reading frame encodes a 224-amino acid
precursor including a 29-residue secretion signal. The predicted
structure of the new protein shares 37% sequence identity with TIMP-1
and 51% identity with TIMP-2 and -3. The protein has a predicted
isoelectric point of 7.34. The open reading frame-directed expression
of TIMP-4 protein in MDA-MB-435 human breast cancer cells showed
metalloproteinase inhibitory activity on reverse zymography. By
Northern analysis, only the adult heart showed abundant TIMP-4
transcripts with a 1.4-kilobase predominant transcript band; very low
levels of the transcripts were detected in the kidney, placenta, colon,
and testes, and no transcripts were detected in the liver, brain, lung,
thymus, and spleen. This unique expression pattern suggests that TIMP-4
may function in a tissue-specific fashion in extracellular matrix
homeostasis.
INTRODUCTION Matrix metalloproteinases (MMPs)1 play
a critical role in ECM homeostasis. Controlled remodeling of the ECM is
an essential aspect in the process of normal development, and
deregulated remodeling has been indicated to have a role in the
etiology of diseases such as arthritis, periodontal disease, and cancer
metastasis (1, 2, 3, 4, 5). The overproduction and unrestrained activity of MMPs
has been linked to malignant conversion of tumor cells (4, 5, 6, 7, 8, 9, 10, 11, 12). The
down-regulation of MMPs may occur at the levels of transcriptional regulation of the genes and activation of secreted proenzymes and
through interaction with specific inhibitor proteins such as TIMPs.
TIMPs are secreted multifunctional proteins that play pivotal roles in
the regulation of ECM metabolism. Their most widely recognized action
is as inhibitors of matrix MMPs. Thus, the net MMP activity in the ECM
is the result of the balance between activated enzyme levels and TIMPs
levels. Augmented MMP activity is associated with the metastatic
phenotype of carcinomas, especially breast cancer (7, 8, 9, 13, 14, 15, 16); the decreased production of TIMP could also result in greater effective enzyme activity and invasive potentials (17, 18, 19). These results suggest
that an increase in the amount of TIMPs relative to MMPs could function
to block tumor cell invasion and metastasis. In fact, tumor cell
invasion and metastasis can be inhibited by up-regulation of TIMP
expression or by an exogenous supply of TIMPs (17, 40, 41, 42, 43, 44).
Three mammalian TIMPs have been characterized at the sequence level:
TIMP-1 (20), TIMP-2 (21), and TIMP-3 (22, 23, 24, 25, 36). The proteins are
classified based on structural similarity to each other as well as
their ability to inhibit matrix metalloproteinases. There have been
other reports of inhibitors of metalloproteases (IMPs) with
characteristics different from these known TIMPs. In some cases these
activities result from alternate forms of the known TIMPs. For
instance, a report describes one IMP present in the conditioned media
of human bladder carcinoma to be a partially glycosylated form of
TIMP-1 and another to be a partially processed and degraded form of
TIMP-2 (25). There are additional reports that describe sources and
characteristics of IMP activity, but the gene products associated with
these activities have not been delineated (26).
Individual TIMP family members may have specific physiological roles.
This notion is supported by several lines of evidence. First, although
TIMPs are essentially interchangeable in their capabilities as
inhibitors of MMPs, they are distinguished by the formation of specific
complexes with different pro-MMPs (27, 28, 29). Secreted MMP-2·TIMP-2 and
MMP-9·TIMP-1 complexes may represent an additional function for TIMPs
in controlling activation of specific latent MMPs. Unlike TIMP-1 and
-2, TIMP-3 has a unique association with the ECM (30). Second, the
expression of TIMP genes is quite different. The TIMP-1 gene is highly
inducible at the transcriptional level in response to many cytokines
and hormones (31, 32, 33, 34). Likewise, TIMP-3 expression is not only induced
in response to mitogenic stimulation but also is subject to cell cycle
regulation (22), suggesting that TIMP-3 expression may represent an
invaluable tool for the analysis of cell cycle progression, terminal
differentiation, and replicative senescence. In contrast, TIMP-2
expression, like that of MMP-2 with which it interacts, is largely
constitutive (21, 37).
Since the introduction of the expressed sequence tag (EST) sequencing
approach, many novel human genes have been discovered and isolated
(38). With the rapidly growing repertoire of human ESTs, we took
advantage of automated EST sequence analysis to identify novel
TIMP-related genes. We describe here the full-length sequence of a
novel member of the TIMP family, and we examined the expression of this
new member, TIMP-4, in a variety of tissues. We have also demonstrated
an MMP inhibitory activity of the expressed TIMP-4 protein.
MATERIALS AND METHODS Restriction enzymes, T7 polymerase, a random
primer DNA-labeling kit, and digoxigenin-labeled nucleotides were
obtained from Boehringer Mannhem. [32P]dATP was purchased
from Amersham Corp.
We have used EST analysis to search for a new TIMP. A
data base containing approximately 500,000 human partial cDNA
sequences (expressed sequence tags) has been established in a
collaborative effort between the Institute for Genomic Research and
Human Genome Science, Inc., using high throughput automated DNA
sequence analysis of randomly selected human cDNA clones (38).
Sequences of TIMP-related genes were searched for using the blastn and
tblastn algorithms (39). An EST from a human brain library, which
demonstrated homology to TIMPs, was completely sequenced and found to
be a partial clone lacking the sequence at the 5 Total RNA was extracted from tissues
according to the method of Chomczynski and Sacchi (45). The RNA from
human breast cancer cells was prepared using the RNAzol B RNA isolation
kit (Tel-Test, Inc.) based on the manufacturer's instructions. Equal
aliquots of RNA were electrophoresed in a 1.2% agarose gel containing
formaldehyde and transferred to a nylon membrane (Boehringer Mannheim).
The membrane was prehybridized with ExpressHyb hybridization solution (Clontech, Inc.) at 68 °C for 30 min. The hybridization was carried out in the same solution with a 32P-labeled TIMP-4 probe
(1.5 × 106 cpm/ml) for 1 h at 68 °C. The
membrane was then rinsed in 2 × SSC (1 × SSC constains 0.15 M NaCl and 0.015 M sodium citrate, pH 7.0)
containing 0.05% SDS three times for 30 min at room temperature, followed by two washes with 0.1 × SSC containing 0.1% SDS for 40 min at 50 °C. The full-length TIMP-4 cDNA was isolated from the
Bluescript vector, following EcoRI and XhoI
digestion, and used as a template for preparation of a random-labeled
cDNA probe. The riboprobe is a 390-base segment extending from
nucleotides 800-1,189 (the end of the 3 The human
TIMP-4 full-length sequence was subcloned into the pCI-neo mammalian
expression vector (Promega) downstream of the human cytomegalovirus
promoter to generate the pCITIMP4 expression vector. Forty micrograms
of pCITIMP4 or the control pCI-neo plasmids were transfected into
MDA-MB-435 human breast cancer cells by the calcium phosphate-mediated
method as described previously (46). Thirty G418-resistant individual
clones were selected in the selection medium containing 800 µg/ml
G418, subcloned, and characterized by in situ hybridization
and Northern blot analysis. TIMP-4-producing clones were grown in
serum-free defined medium. The conditioned media were collected at
40 h after culturing cells in serum-free Dulbecco's modified
Eagle's medium, concentrated approximately 10-fold using an Amicon
hollow fiber concentrator with a Mr 10,000 cutoff. The inhibitory activity was subsequently analyzed on reverse
zymography SDS-polyacrylamide gel electrophoresis.
Samples of
conditioned media from TIMP-4 -producing clones and control clones were
adjusted to the same protein concentration and electrophoresed on a
0.1% SDS, 12% polyacrylamide protease substrate gel (47). The gel was
incubated in collagenase buffer (50 mM Tris, pH 7.4, 0.2 M NaCl, 5 mM CaCl2, 1% Triton
X-100, and 0.7 µg/ml of recombinant MMP2) at 37 °C overnight to
allow digestion of gelatin in the gel. The MMP inhibitory activities of
samples were visualized by Commassie Blue R-250
(Sigma) staining and destaining as described
previously (48).
RESULTS We have searched a data
base of human genes identified by the EST method. The automated
screening revealed an EST from a human brain library with a 45%
sequence homology to the TIMP-2 protein. The clone was completely
sequenced. A putative stop codon was located; however, a start codon
(ATG) could not be located at the 5 The nucleotide sequence determined from this clone and the predicted
corresponding amino acid sequence are shown in Fig. 1. The full-length cDNA sequence contains 1,189 bp with a 672-bp open
reading frame: 59 bp in the 5
The extensive similarity of the predicted amino acid sequence with
TIMPs suggests that the putative new protein is a novel member of the
human TIMP family and should be designated human TIMP-4.
Tissue-specific transcription of TIMP-4 was
examined by Northern blotting on 20 µg of total RNAs from various
human adult tissues (Fig. 3). As expected, the Northern
blot showed maximal TIMP-4 transcript levels in the heart. Using a
full-length cDNA hybridization probe, transcripts of 4.1, 2.1, 1.4, 1.2, and 0.97 kb were detected in heart, with the 1.4-kb band
representing at least 90% of the hybridization signal. Similar bands,
with much lesser accumulations in their relative intensity, were also
obtained in the kidney, pancreas, colon, and testes. By contrast, none of them was present in other specimens analyzed, such as the liver, brain, lung, small intestine, thymus, and spleen. The 1.4-kb TIMP-4 transcript was also detected in RNA isolated from the human breast cancer cell line MDA-MB-231 (Fig. 4). To rule out the
possibility of cross-hybridization with TIMP-1-TIMP-3, an additional
filter with RNA from MDA-MB-231 cells was also hybridized with a 389-bp riboprobe, which represents a specific nucleotide sequence of the
3
Active recombinant
TIMP-4 protein is required for characterization of its biochemical
activity against MMPs and biological functions to inhibit tumor growth
and metastasis. As an initial attempt to evaluate the biological
significance of TIMP-4 to inhibit cancer growth and metastasis, we have
transfected the TIMP-4 full-length cDNA into the highly tumorigenic
MDA-MB-435 human breast cancer cells. Three positive clones have been
selected and expressed high levels of the TIMP-4 transcript (Fig.
5A). Conditioned media from two
TIMP-4-positive clone and one control clone were collected, concentrated, and analyzed for metalloproteinase inhibitory activity by
reverse zymography. Fig. 5B shows that the conditioned media from TIMP-4-producing clones contained a prominent MMP inhibitory activity at the 22-kDa band in a nonreducing gelatin-containing SDS
gel. In contrast, no such activity was observed in the conditioned medium form control MDA-MB-435 cells, suggesting that no endogenous TIMP activities were detectable in the same conditions for detection of
recombinant TIMP-4 activity.
DISCUSSION The work described here introduces a new member of the TIMP
family, to which we confer the title TIMP-4 because of its high sequence homology to the TIMP family, 12 conserved cysteine residues, and the expressed MMP inhibitory activity.
The classic approach to identifying novel proteins begins with the
discovery of an interesting biological activity. This protein is then
purified and biochemically characterized, and subsequently, the gene is
cloned. Since the introduction of the EST sequencing approach and the
availability of tens of thousands of ESTs, researchers can now shift
their attention to high throughput cDNA cloning in conjunction with
structural similarity analysis as an accelerated method of protein
discovery. In this regard, the nucleic acid sequences of randomly
picked cDNAs from established EST data bases are searched and
analyzed by the BLAST program for sequence similarity to the protein of
interest. Where similarities are detected, it is possible to make
functional inferences concerning the encoded protein based on what is
known about the function of the matched sequences. Using this approach,
we identified an EST with high sequence homology to TIMP-2 and,
subsequently, the novel TIMP-4 gene was cloned using this EST as a
probe.
The predicted protein structure of TIMP-4 shows several interesting
features. First, as expected, essential features of other TIMPs are
conserved, including the location of 12 Cys residues, as well as their
relative spacing and the presence of a 29-amino acid leader sequence,
which presumably is cleaved to produce the mature protein (13). Second,
the mature protein has an expected size of 22 kDa, which is similar to
the sizes of TIMP proteins. Expressed rTIMP-4 protein migrates as a
24-kDa protein by reverse zymography SDS-polyacrylamide gel
electrophoresis at nonreducing conditions, which is consistent with
that obtained for other TIMPs (25). Third, the deduced amino acid
sequence of TIMP-4 predicts a protein with an isoelectric point of
7.34, the most neutral human TIMP protein at the physiological
condition (pH 7.4) comparing with values of 8.00, 6.45, and 9.04 for
human TIMP-1, TIMP-2, and TIMP-3, respectively (24). Fourth, as
expected, TIMP-4 has a highly conserved amino-terminal domain similar
to other TIMPs. The amino-terminal 126 amino acid residues of mature
TIMP-1 (51) and the amino-terminal 127 residues of mature TIMP-2 (52,
35) have been shown to be adequate for the inhibition of MMPs,
suggesting that this part of the proteins is functionally critical for
inhibition of MMPs. In this region, the first 22 amino acids of the
mature proteins is the most conserved among the TIMPs; 16 of the first 22 amino acids (73%) are identical among human TIMP-1-TIMP-3. However, the first 22 amino acids of mature TIMP-4 show a decreased sequence identity with other TIMPs: 63% identical to TIMP-1 and TIMP-2
and 59% identical to TIMP-3. The consensus sequence
CXCXPXHPQXAFCNXDXVIRAK (single amino acid code; X, any amino acid) has
been proposed to serve a diagnostic hallmark of the TIMPs being present
in TIMP-1-TIMP-3 (36). Because TIMP-4 has a less conserved sequence in
this region, with only 12 of 22 amino acids identical in all four
TIMPs, we suggest the use of consensus sequence VIRAK (positions
47-51; Fig. 2) as a diagnostic hallmark of the TIMP family. We have
shown that TIMP-4 is more homologous to TIMP-2 and TIMP-3 than to
TIMP-1.
Tissue expression of TIMP-4 appears limited. Although large amounts of
transcript were detected in the heart, much lower levels of expression
were detected in the kidney, pancreas, colon, and testes; no TIMP-4
transcripts were detected in other tissues, such as liver, brain, lung,
thymus, small intestine, and spleen. TIMP-4 may function in a
tissue-specific fashion as part of an acute response to tissue
remodeling. It is interesting to note that the highest level of TIMP-4
expression is seen in the heart, in which human cancer metastasis
rarely occurs. The possibility that the high expression of TIMP-4 in
the heart may contribute the inability of malignant cells to invade
needs further consideration.
We have expressed TIMP-4 in MDA-MB-435 human breast cancer cells in an
effort to investigate the biological significance of this new TIMP in
tumor growth and metastasis. Since TIMPs block the activities of MMPs,
the net inhibitory activity of TIMPs might be important in preventing
malignant progression from the benign to the metastatic phenotype. In
fact, tumor cell invasion and metastasis can be blocked by
up-regulation of TIMP expression or an exogenous supply of TIMPs (17,
40, 41, 42, 43, 44). Alternatively, down-regulation of TIMP-1 and -2 has been reported to contribute significantly to the invasive potential of human
glioblastoma (19). We have analyzed the MMP inhibitory activities of
the expressed rTIMP-4 from the conditioned media of transfected clones.
As expected, rTIMP-4 proteins expressed from human breast cancer cells
possess an inhibitory activity against MMP and are secreted
extracellularly, thus confirming that the novel protein is a new member
of the TIMP family.
In summary, we have cloned and sequenced a novel human TIMP gene
designated TIMP-4, the expression of which is tissue-specific. We have
also presented evidence indicating the MMP inhibitory activity of the
expressed TIMP-4 protein.
FOOTNOTES Acknowledgments We thank Dr. W. G. Stetler-Stevenson for
providing rMMP-2, Drs. Amy Sang and Robert Bienkowski for discussion on
the manuscript, and Jane Shirreffs for reading the manuscript.
REFERENCES
Volume 271, Number 48,
Issue of November 29, 1996
pp. 30375-30380
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,, and
Human Genome Sciences, Inc.,
Rockville, Maryland 20850-3338 and § Department of
Pediatrics, Long Island Jewish Medical Center, The Long Island
Campus for the Albert Einstein College of Medicine,
New Hyde Park, New York 11042
-end. The coding
region and 3-untranslated region of this clone were excised from the Bluescript vector by digestion with the restriction endonucleases EcoRI and XhoI and used to generate a
radiolabeled probe. This probe was used to screen a Northern blot of
total RNAs from several human tissues. The highest level of expression
of the putative novel TIMP was noted in RNA from adult heart. We next
generated a cDNA library from human heart. Poly(A) mRNA from
heart tissue was obtained using Oligotex beads. Five micrograms of this
mRNA were used to construct a directional cDNA library in the
Stratagene Unizap vector using the Stratagene cDNA library kit. One
million clones of the primary library were amplified, and an aliquot
was excised to yield Bluescript SK plasmid clones. These clones were screened with the probe generated by EcoRI and
XhoI digestion of the positive clone from a human brain
library as described above. Positive clones were rescreened, both by
hybridization and polymerase chain reaction analysis, using a
Bluescript reverse primer and an antisense primer
(5-GACTGTCCACTTGGCACTTCT-3) specific for the putative TIMP-related
gene in the 3-untranslated region. The full-length cDNA was
completely sequenced using ABI 373a automated fluorescent sequencer
protocols.
-end of the cDNA). This
riboprobe, which covers 85% of the 3-untranslated region, was
generated by PstI digestion of the Bluscript vector,
followed by RNA synthesis with T7 polymerase.
-end. The length of the open
reading frame was also shorter than expected for a 22-28-kDa protein
in the TIMP family. Therefore, it was concluded that this cDNA
clone did not encode the entire putative TIMP protein, and that a
segment at the 5-end containing the start codon was missing. To obtain
the full-length sequence of the putative new TIMP gene, the identified
cDNA clone was prepared as a probe and was used to investigate the
expression of this new putative TIMP gene in a variety of human tissues
by Northern blot analysis. Because the highest expression of this new
putative TIMP gene was identified in human heart, we next generated a
cDNA phage library from a human adult heart and screened 1 million clones for an additional 5-sequence. As a result, a number of clones
were identified, and the longest of these was sequenced and found to
contain the full-length cDNA sequence of the putative new TIMP
gene.
-untranslated region and 458 bp of a
3-untranslated sequence. The open reading frame extends from the
initiation A60TG codon to TAG732 stop. The open reading frame encodes a
protein of 224 amino acids. A hydrophobic leader sequence at the amino
terminus conforms to a consensus signal peptide with a predicted
cleavage site following an alanine residue located at position 29 in
the precursor (Fig. 1). Removal of the signal sequence results in a
mature protein of 195 amino acids, having a calculated molecular mass
of 22 kDa, which is in close agreement with the molecular mass range of
the TIMP family. The deduced amino acid sequence predicts a protein
with an isoelectric point of 7.34. Comparison of the predicted amino
acid sequence with the sequences of human TIMP-related proteins is
shown in Fig. 2. After optimal alignment, the putative
protein shows 37% sequence identity and 57% similarity to TIMP-1 and
51% identity and 70% similarity to TIMP-2 and -3. These calculations
do not take into account the significance of any gaps in the
alignments. The predicted protein structure of the putative new protein
shares several essential features that are characteristic of the TIMP family, including 12 completely conserved cysteine residues in the
corresponding positions that form intrachain disulfide bonds that fold
the protein into a two domain structure (49). The presence of a
consensus sequence, VIRAK, which has been proposed to serve a hallmark
of the TIMP family (36, 50), was also observed in the most conserved
first 22 amino acids located at the amino-terminal region.
Fig. 1.
TIMP-4 cDNA sequence. The
full-length cDNA was sequenced using the ABI 373a automated
fluorescent sequencer method. The deduced amino acid sequence is shown
under the DNA sequence. *, the translation termination codon (TAG).
The putative mature protein cleavage site is underlined at
position 29 for alanine. Numbers refer to nucleic acid
positions. The sequence has been deposited in GenBank with the
accession number U76456[GenBank].
[View Larger Version of this Image (61K GIF file)]
Fig. 2.
Comparison of the predicted amino acid
sequence of human TIMP-4 with human TIMP-1-TIMP-3. The available
amino acid sequence of TIMP-1 (accession number P01033[GenBank]), TIMP-2 (accession number P16035[GenBank]), and TIMP-3 (accession number P35625[GenBank]) were
obtained from the SwissProt data base and aligned with the TIMP-4
deduced sequence using the clustal method of the MegAlign program from
the DNASTAR software package. Conserved bases are boxed; the
29-amino acid putative signal sequence is shown between two
triangles (
), and the 12 conserved cysteine residues are
labeled with arrows.
[View Larger Version of this Image (66K GIF file)]
-untranslated TIMP-4. As shown in Fig. 4B, the riboprobe recognized the same bands in the RNA from MDA-MB-231 cells as the
complete DNA probe, thus suggesting that the 1.4-kb transcript corresponds to TIMP-4.
Fig. 3.
Expression of the TIMP-4 gene in a variety of
normal adult human tissues. Twenty micrograms of total RNA were
analyzed in Northern blotting. A strong hybridizing band of 1.4 kilobases was recognized in the lane corresponding to RNA from adult
heart. Additional bands with much lower intensities corresponding to mRNA species of about 4.1, 2.1, 1.2, and 0.97 kb were also
detected. The integrity of the RNA samples was ascertained by direct
visualization of the ribosomal RNAs in the stained gel.
[View Larger Version of this Image (73K GIF file)]
Fig. 4.
Northern analysis of TIMP-4 expression in
human breast cancer cells. RNAs were isolated and subjected to
Northern analysis by hybridization with either a full-length cDNA
probe (A) or a 390-base riboprobe, which represents a
specific nucleotide sequence of the 3-untranslated TIMP-4
(C). The integrity of the RNA was ascertained by
hybridization with a housekeeping gene, 36B4 (B). Each lane
contained 20 µg of total RNA. Northern analysis failed to detect the
TIMP-4 transcript in most breast cancer cell lines, except MDA-MB-231
cells, which showed a strong 1.4-kb TIMP-4 transcript; a very weak
hybridization signal was also detected in MDA-MB-436 cells.
[View Larger Version of this Image (68K GIF file)]
Fig. 5.
Metalloproteinase inhibitory activities
produced by transforming human breast cancer cells. The human
breast cancer cell line MDA-MB-435 was transfected with either the
pCITIMP4 plasmid containing the full-length TIMP-4 cDNA or the
control pCI-neo plasmid, and the TIMP-4 positive clones were selected as described under "Materials and Methods." A, Northern
blot of RNAs from both control and TIMP-4 transfected clones. Total
RNAs were isolated from three control pCI-neo transfected clones
(N1-N3) and four TIMP-4-transfected clones
(P1-P4) and then subjected to Northern blot analysis with a
random-labeled, full-length TIMP-4 probe. Strong TIMP-4 transcripts
were detected in three of four transfected clones; clone P3
shows low level TIMP-4 expression. In contrast, no endogenous TIMP-4
transcripts were detected in any of the control clones. The integrity
of the RNAs and loading control were ascertained by hybridization with
a housekeeping gene, 36B4 (B). C, analysis of MMP
inhibitory activity by reverse zymography. Conditioned media were
prepared from one control clone (N1) and two TIMP-4-producing clones
(P1 and P4), concentrated, and analyzed by protease substrate gel
electrophoresis as described under "Materials and Methods."
Lane 1, clone P1; lane 2, clone N1; lane
3, clone P4. Arrow, molecular mass of the expressed
TIMP-4 protein.
[View Larger Version of this Image (41K GIF file)]
¶
To whom correspondence should be addressed: Pediatric Research
Center, Schneider Children Hospital, Long Island Jewish Medical Center,
New Hyde Park, NY 11042. Tel.: 718-470-3086; Fax: 718-470-6744; E-mail:
Shi{at}aecom.yu.edu.
1
The abbreviations used are: MMP, matrix
metalloproteinase; TIMP, tissue inhibitor of metalloproteinases; IMP,
inhibitor of metalloproteases; ECM, extracellular matrix; EST,
expressed sequence tag; bp, base pair; kb, kilobase.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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M. Rapti, V. Knauper, G. Murphy, and R. A. Williamson Characterization of the AB Loop Region of TIMP-2: INVOLVEMENT IN PRO-MMP-2 ACTIVATION J. Biol. Chem., August 18, 2006; 281(33): 23386 - 23394. [Abstract] [Full Text] [PDF]
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 R. Pilka, V. Noskova, H. Domanski, C. Andersson, S. Hansson, and B. Casslen Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid Mol. Hum. Reprod., August 1, 2006; 12(8): 497 - 503. [Abstract] [Full Text] [PDF]
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J. L. English, Z. Kassiri, I. Koskivirta, S. J. Atkinson, M. Di Grappa, P. D. Soloway, H. Nagase, E. Vuorio, G. Murphy, and R. Khokha Individual Timp Deficiencies Differentially Impact Pro-MMP-2 Activation J. Biol. Chem., April 14, 2006; 281(15): 10337 - 10346. [Abstract] [Full Text] [PDF]
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 H.-J. Kwak, M.-J. Park, H. Cho, C.-M. Park, S.-I. Moon, H.-C. Lee, I.-C. Park, M.-S. Kim, C. H. Rhee, and S.-I. Hong Transforming Growth Factor-{beta}1 Induces Tissue Inhibitor of Metalloproteinase-1 Expression via Activation of Extracellular Signal-Regulated Kinase and Sp1 in Human Fibrosarcoma Cells Mol. Cancer Res., March 1, 2006; 4(3): 209 - 220. [Abstract] [Full Text] [PDF]
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 D. Vanhoutte, M. Schellings, Y. Pinto, and S. Heymans Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window Cardiovasc Res, February 15, 2006; 69(3): 604 - 613. [Abstract] [Full Text] [PDF]
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C. M. Dollery and P. Libby Atherosclerosis and proteinase activation Cardiovasc Res, February 15, 2006; 69(3): 625 - 635. [Abstract] [Full Text] [PDF]
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 W. T. Wu, C.-N. Chen, C. I. Lin, J. H. Chen, and H. Lee Lysophospholipids Enhance Matrix Metalloproteinase-2 Expression in Human Endothelial Cells Endocrinology, August 1, 2005; 146(8): 3387 - 3400. [Abstract] [Full Text] [PDF]
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 B. Menon, M. Singh, and K. Singh Matrix metalloproteinases mediate {beta}-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes Am J Physiol Cell Physiol, July 1, 2005; 289(1): C168 - C176. [Abstract] [Full Text] [PDF]
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A. M. Deschamps, W. M. Yarbrough, C. E. Squires, R. A. Allen, D. M. McClister, K. B. Dowdy, J. E. McLean, J. T. Mingoia, J. A. Sample, R. Mukherjee, et al. Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Reperfusion: Relation to Interstitial Membrane Type-1 Matrix Metalloproteinase Activity Circulation, March 8, 2005; 111(9): 1166 - 1174. [Abstract] [Full Text] [PDF]
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J. D. Lovelock, A. H. Baker, F. Gao, J.-F. Dong, A. L. Bergeron, W. McPheat, N. Sivasubramanian, and D. L. Mann Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H461 - H468. [Abstract] [Full Text] [PDF]
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 M. M. Lalu, E. Pasini, C. J. Schulze, M. Ferrari-Vivaldi, G. Ferrari-Vivaldi, T. Bachetti, and R. Schulz Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart Eur. Heart J., January 1, 2005; 26(1): 27 - 35. [Abstract] [Full Text] [PDF]
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J. S. Ikonomidis, J. W. Hendrick, A. M. Parkhurst, A. R. Herron, P. G. Escobar, K. B. Dowdy, R. E. Stroud, E. Hapke, M. R. Zile, and F. G. Spinale Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H149 - H158. [Abstract] [Full Text] [PDF]
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 V. Polyakova, S. Hein, S. Kostin, T. Ziegelhoeffer, and J. Schaper Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression J. Am. Coll. Cardiol., October 19, 2004; 44(8): 1609 - 1618. [Abstract] [Full Text] [PDF]
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 D. D. Mruk and C. Y. Cheng Sertoli-Sertoli and Sertoli-Germ Cell Interactions and Their Significance in Germ Cell Movement in the Seminiferous Epithelium during Spermatogenesis Endocr. Rev., October 1, 2004; 25(5): 747 - 806. [Abstract] [Full Text] [PDF]
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R. Pilka, H. Domanski, S. Hansson, P. Eriksson, and B. Casslen Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26 Mol. Hum. Reprod., September 1, 2004; 10(9): 641 - 650. [Abstract] [Full Text] [PDF]
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 K. Kaikita, T. Hayasaki, T. Okuma, W. A. Kuziel, H. Ogawa, and M. Takeya Targeted Deletion of CC Chemokine Receptor 2 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction Am. J. Pathol., August 1, 2004; 165(2): 439 - 447. [Abstract] [Full Text] [PDF]
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 Y.-G. Zhao, A.-Z. Xiao, H. I. Park, R. G. Newcomer, M. Yan, Y.-G. Man, S. C. Heffelfinger, and Q.-X. A. Sang Endometase/Matrilysin-2 in Human Breast Ductal Carcinoma in Situ and Its Inhibition by Tissue Inhibitors of Metalloproteinases-2 and -4: A Putative Role in the Initiation of Breast Cancer Invasion Cancer Res., January 15, 2004; 64(2): 590 - 598. [Abstract] [Full Text] [PDF]
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R. E. Chapman and F. G. Spinale Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H1 - H10. [Full Text] [PDF]
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 D. Krex, H. Rohl, I. R. Konig, A. Ziegler, H. K. Schackert, and G. Schackert Tissue Inhibitor of Metalloproteinases-1, -2, and -3 Polymorphisms in a White Population With Intracranial Aneurysms Stroke, December 1, 2003; 34(12): 2817 - 2821. [Abstract] [Full Text] [PDF]
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T. E. Curry Jr. and K. G. Osteen The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle Endocr. Rev., August 1, 2003; 24(4): 428 - 465. [Abstract] [Full Text] [PDF]
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C. Boixel, V. Fontaine, C. Rucker-Martin, P. Milliez, L. Louedec, J.-B. Michel, M.-P. Jacob, and S. N. Hatem Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat J. Am. Coll. Cardiol., July 16, 2003; 42(2): 336 - 344. [Abstract] [Full Text] [PDF]
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E. M. Wilson, S. L. Moainie, J. M. Baskin, A. S. Lowry, A. M. Deschamps, R. Mukherjee, T. S. Guy, M. G. St John-Sutton, J. H. Gorman III, L. H. Edmunds Jr, et al. Region- and Type-Specific Induction of Matrix Metalloproteinases in Post-Myocardial Infarction Remodeling Circulation, June 10, 2003; 107(22): 2857 - 2863. [Abstract] [Full Text] [PDF]
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C. J. Schulze, W. Wang, W. L. Suarez-Pinzon, J. Sawicka, G. Sawicki, and R. Schulz Imbalance Between Tissue Inhibitor of Metalloproteinase-4 and Matrix Metalloproteinases During Acute Myoctardial Ischemia-Reperfusion Injury Circulation, May 20, 2003; 107(19): 2487 - 2492. [Abstract] [Full Text] [PDF]
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J. Zhang, Y.-G. Zhao, Y.-J. Cao, Q.-X. A. Sang, and E.-K. Duan Expression and implications of tissue inhibitor of metalloproteinases-4 in mouse embryo Mol. Hum. Reprod., March 1, 2003; 9(3): 143 - 149. [Abstract] [Full Text] [PDF]
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C. Qun Gao, G. Sawicki, W. L Suarez-Pinzon, T. Csont, M. Wozniak, P. Ferdinandy, and R. Schulz Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction Cardiovasc Res, February 1, 2003; 57(2): 426 - 433. [Abstract] [Full Text] [PDF]
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 K. S. Simpson, C. M. Komar, and T. E. Curry Jr Localization and Expression of Tissue Inhibitor of Metalloproteinase-4 in the Immature Gonadotropin-Stimulated and Adult Rat Ovary Biol Reprod, January 1, 2003; 68(1): 214 - 221. [Abstract] [Full Text] [PDF]
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H. S.-T. Kai, G. S. Butler, C. J. Morrison, A. E. King, G. R. Pelman, and C. M. Overall Utilization of a Novel Recombinant Myoglobin Fusion Protein Expression System to Characterize the Tissue Inhibitor of Metalloproteinase (TIMP)-4 and TIMP-2 C-terminal Domain and Tails by Mutagenesis. THE IMPORTANCE OF ACIDIC RESIDUES IN BINDING THE MMP-2 HEMOPEXIN C DOMAIN J. Biol. Chem., December 6, 2002; 277(50): 48696 - 48707. [Abstract] [Full Text] [PDF]
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 M. Pauschinger, K. Chandrasekharan, J. Li, W. Poller, M. Noutsias, C. Tschope, and H.-P. Schultheiss Inflammation and extracellular matrix protein metabolism: two sides of myocardial remodelling Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I49 - I53. [Abstract] [PDF]
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F. Arechavaleta-Velasco, D. Ogando, S. Parry, and F. Vadillo-Ortega Production of Matrix Metalloproteinase-9 in Lipopolysaccharide-Stimulated Human Amnion Occurs Through an Autocrine and Paracrine Proinflammatory Cytokine-Dependent System Biol Reprod, December 1, 2002; 67(6): 1952 - 1958. [Abstract] [Full Text] [PDF]
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 M. J. Hunt, G. M. Aru, M. R. Hayden, C. K. Moore, B. D. Hoit, and S. C. Tyagi Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L239 - L245. [Abstract] [Full Text] [PDF]
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J. Zhang, Y.-J. Cao, Y.-G. Zhao, Q.-X. A. Sang, and E.-K. Duan Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3 Mol. Hum. Reprod., July 1, 2002; 8(7): 659 - 666. [Abstract] [Full Text] [PDF]
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M. Bond, G. Murphy, M. R. Bennett, A. C. Newby, and A. H. Baker Tissue Inhibitor of Metalloproteinase-3 Induces a Fas-associated Death Domain-dependent Type II Apoptotic Pathway J. Biol. Chem., April 12, 2002; 277(16): 13787 - 13795. [Abstract] [Full Text] [PDF]
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W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
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 H. Ihn, K. Yamane, Y. Asano, M. Kubo, and K. Tamaki IL-4 Up-Regulates the Expression of Tissue Inhibitor of Metalloproteinase-2 in Dermal Fibroblasts Via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway J. Immunol., February 15, 2002; 168(4): 1895 - 1902. [Abstract] [Full Text] [PDF]
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M. N. Holten-Andersen, I. J. Christensen, H. J. Nielsen, R. W. Stephens, V. Jensen, O. H. Nielsen, S. Sorensen, J. Overgaard, H. Lilja, A. Harris, et al. Total Levels of Tissue Inhibitor of Metalloproteinases 1 in Plasma Yield High Diagnostic Sensitivity and Specificity in Patients with Colon Cancer Clin. Cancer Res., January 1, 2002; 8(1): 156 - 164. [Abstract] [Full Text] [PDF]
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 E. Oelmann, H. Herbst, M. Zuhlsdorf, O. Albrecht, A. Nolte, C. Schmitmann, O. Manzke, V. Diehl, H. Stein, and W. E. Berdel Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin/Reed-Sternberg cells Blood, January 1, 2002; 99(1): 258 - 267. [Abstract] [Full Text] [PDF]
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A. Hozumi, Y. Nishimura, T. Nishiuma, Y. Kotani, and M. Yokoyama Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathway Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1444 - L1452. [Abstract] [Full Text] [PDF]
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G. C. Durkan, J. E. Nutt, P. H. Rajjayabun, D. E. Neal, J. Lunec, and J. K. Mellon Prognostic Significance of Matrix Metalloproteinase-1 and Tissue Inhibitor of Metalloproteinase-1 in Voided Urine Samples from Patients with Transitional Cell Carcinoma of the Bladder Clin. Cancer Res., November 1, 2001; 7(11): 3450 - 3456. [Abstract] [Full Text] [PDF]
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 I. Mayers, T. Hurst, L. Puttagunta, A. Radomski, T. Mycyk, G. Sawicki, D. Johnson, and M. W. Radomski Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts J. Thorac. Cardiovasc. Surg., October 1, 2001; 122(4): 746 - 752. [Abstract] [Full Text] [PDF]
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E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]
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H. Wang, Q. Li, L. Shao, and C. Zhu Expression of Matrix Metalloproteinase-2, -9, -14, and Tissue Inhibitors of Metalloproteinase-1, -2, -3 in the Endometrium and Placenta of Rhesus Monkey (Macaca mulatta) During Early Pregnancy Biol Reprod, July 1, 2001; 65(1): 31 - 40. [Abstract] [Full Text] [PDF]
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K. S. Simpson, M. J. Byers, and T. E. Curry Jr. Spatiotemporal Messenger Ribonucleic Acid Expression of Ovarian Tissue Inhibitors of Metalloproteinases throughout the Rat Estrous Cycle Endocrinology, May 1, 2001; 142(5): 2058 - 2069. [Abstract] [Full Text]
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H. F. Bigg, C. J. Morrison, G. S. Butler, M. A. Bogoyevitch, Z. Wang, P. D. Soloway, and C. M. Overall Tissue Inhibitor of Metalloproteinases-4 Inhibits But Does Not Support the Activation of Gelatinase A via Efficient Inhibition of Membrane Type 1-Matrix Metalloproteinase Cancer Res., May 1, 2001; 61(9): 3610 - 3618. [Abstract] [Full Text]
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Y. Jiang, M. Wang, M. Y. Çeliker, Y. E. Liu, Q. X. Amy Sang, I. D. Goldberg, and Y. E. Shi Stimulation of Mammary Tumorigenesis by Systemic Tissue Inhibitor of Matrix Metalloproteinase 4 Gene Delivery Cancer Res., March 1, 2001; 61(6): 2365 - 2370. [Abstract] [Full Text]
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 C S Cleaver, A D Rowan, and T E Cawston Interleukin 13 blocks the release of collagen from bovine nasal cartilage treated with proinflammatory cytokines Ann Rheum Dis, February 1, 2001; 60(2): 150 - 157. [Abstract] [Full Text] [PDF]
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H. Huang, S. Colella, M. Kurrer, Y. Yonekawa, P. Kleihues, and H. Ohgaki Gene Expression Profiling of Low-Grade Diffuse Astrocytomas by cDNA Arrays Cancer Res., December 1, 2000; 60(24): 6868 - 6874. [Abstract] [Full Text]
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M. N. Holten-Andersen, R. W. Stephens, H. J. Nielsen, G. Murphy, I. J. Christensen, W. Stetler-Stevenson, and N. Brunner High Preoperative Plasma Tissue Inhibitor of Metalloproteinase-1 Levels Are Associated with Short Survival of Patients with Colorectal Cancer Clin. Cancer Res., November 1, 2000; 6(11): 4292 - 4299. [Abstract] [Full Text] [PDF]
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M. Selman, V. Ruiz, S. Cabrera, L. Segura, R. Ramirez, R. Barrios, and A. Pardo TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L562 - L574. [Abstract] [Full Text] [PDF]
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Y. Yoshihara, H. Nakamura, K.'i. Obata, H. Yamada, T. Hayakawa, K. Fujikawa, and Y. Okada Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis Ann Rheum Dis, June 1, 2000; 59(6): 455 - 461. [Abstract] [Full Text]
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J. O. Stracke, M. Hutton, M. Stewart, A. M. Pendas, B. Smith, C. Lopez-Otin, G. Murphy, and V. Knauper Biochemical Characterization of the Catalytic Domain of Human Matrix Metalloproteinase 19. EVIDENCE FOR A ROLE AS A POTENT BASEMENT MEMBRANE DEGRADING ENZYME J. Biol. Chem., May 12, 2000; 275(20): 14809 - 14816. [Abstract] [Full Text] [PDF]
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Y. Y. Li, C. F. McTiernan, and A. M. Feldman Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res, May 1, 2000; 46(2): 214 - 224. [Abstract] [Full Text] [PDF]
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F. G Spinale, M. L Coker, B. R Bond, and J. L Zellner Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target Cardiovasc Res, May 1, 2000; 46(2): 225 - 238. [Abstract] [Full Text] [PDF]
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H. Li, H. Simon, T. M.A. Bocan, and J.T. Peterson MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE- and MMP-inhibition Cardiovasc Res, May 1, 2000; 46(2): 298 - 306. [Abstract] [Full Text] [PDF]
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J.T. Peterson, H. Li, L. Dillon, and J. W. Bryant Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat Cardiovasc Res, May 1, 2000; 46(2): 307 - 315. [Abstract] [Full Text] [PDF]
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J. D. Mott, C. L. Thomas, M. T. Rosenbach, K. Takahara, D. S. Greenspan, and M. J. Banda Post-translational Proteolytic Processing of Procollagen C-terminal Proteinase Enhancer Releases a Metalloproteinase Inhibitor J. Biol. Chem., January 14, 2000; 275(2): 1384 - 1390. [Abstract] [Full Text] [PDF]
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Y. Nagatomo, B. A. Carabello, M. L. Coker, P. J. McDermott, S. Nemoto, M. Hamawaki, and F. G. Spinale Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H151 - H161. [Abstract] [Full Text] [PDF]
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R. A. Williamson, F. W. Muskett, M. J. Howard, R. B. Freedman, and M. D. Carr The Effect of Matrix Metalloproteinase Complex Formation on the Conformational Mobility of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) J. Biol. Chem., December 24, 1999; 274(52): 37226 - 37232. [Abstract] [Full Text] [PDF]
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H. R. Lijnen, P. Soloway, and D. Collen Tissue Inhibitor of Matrix Metalloproteinases-1 Impairs Arterial Neointima Formation After Vascular Injury in Mice Circ. Res., December 3, 1999; 85(12): 1186 - 1191. [Abstract] [Full Text] [PDF]
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M. Rouis, C. Adamy, N. Duverger, P. Lesnik, P. Horellou, M. Moreau, F. Emmanuel, J. M. Caillaud, P. M. Laplaud, C. Dachet, et al. Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-1 Reduces Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice Circulation, August 3, 1999; 100(5): 533 - 540. [Abstract] [Full Text] [PDF]
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G. S. Butler, M. Hutton, B. A. Wattam, R. A. Williamson, V. Knauper, F. Willenbrock, and G. Murphy The Specificity of TIMP-2 for Matrix Metalloproteinases Can Be Modified by Single Amino Acid Mutations J. Biol. Chem., July 16, 1999; 274(29): 20391 - 20396. [Abstract] [Full Text] [PDF]
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G. S. Butler, S. S. Apte, F. Willenbrock, and G. Murphy Human Tissue Inhibitor of Metalloproteinases 3 Interacts with Both the N- and C-terminal Domains of Gelatinases A and B. REGULATION BY POLYANIONS J. Biol. Chem., April 16, 1999; 274(16): 10846 - 10851. [Abstract] [Full Text] [PDF]
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Q. Meng, V. Malinovskii, W. Huang, Y. Hu, L. Chung, H. Nagase, W. Bode, K. Maskos, and K. Brew Residue 2 of TIMP-1 Is a Major Determinant of Affinity and Specificity for Matrix Metalloproteinases but Effects of Substitutions Do Not Correlate with Those of the Corresponding P1' Residue of Substrate J. Biol. Chem., April 9, 1999; 274(15): 10184 - 10189. [Abstract] [Full Text] [PDF]
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Y. Y. Li, C. F. McTiernan, and A. M. Feldman Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells Cardiovasc Res, April 1, 1999; 42(1): 162 - 172. [Abstract] [Full Text] [PDF]
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C. M. Dollery, J. R. McEwan, M. Wang, Q. A. Sang, Y. E. Liu, and Y. E. Shi TIMP-4 Is Regulated by Vascular Injury in Rats Circ. Res., March 19, 1999; 84(5): 498 - 504. [Abstract] [Full Text] [PDF]
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C. M. Overall, A. E. King, D. K. Sam, A. D. Ong, T. T. Y. Lau, U. M. Wallon, Y. A. DeClerck, and J. Atherstone Identification of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) Binding Site on the Hemopexin Carboxyl Domain of Human Gelatinase A by Site-directed Mutagenesis. THE HIERARCHICAL ROLE IN BINDING TIMP-2 OF THE UNIQUE CATIONIC CLUSTERS OF HEMOPEXIN MODULES III AND IV J. Biol. Chem., February 12, 1999; 274(7): 4421 - 4429. [Abstract] [Full Text] [PDF]
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M. Moreau, I. Brocheriou, L. Petit, E. Ninio, M. J. Chapman, and M. Rouis Interleukin-8 Mediates Downregulation of Tissue Inhibitor of Metalloproteinase-1 Expression in Cholesterol-Loaded Human Macrophages : Relevance to Stability of Atherosclerotic Plaque Circulation, January 26, 1999; 99(3): 420 - 426. [Abstract] [Full Text] [PDF]
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L. Song, D. G. Porter, and B. L. Coomber Production of Gelatinases and Tissue Inhibitors of Matrix Metalloproteinases by Equine Ovarian Stromal Cells In Vitro Biol Reprod, January 1, 1999; 60(1): 1 - 7. [Abstract] [Full Text]
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 G I Murray, M E Duncan, E Arbuckle, W T Melvin, and J E Fothergill Matrix metalloproteinases and their inhibitors in gastric cancer Gut, December 1, 1998; 43(6): 791 - 797. [Abstract] [Full Text] [PDF]
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W. Q. Liand and M. Zafarullah Oncostatin M Up-Regulates Tissue Inhibitor of Metalloproteinases-3 Gene Expression in Articular Chondrocytes via De Novo Transcription, Protein Synthesis, and Tyrosine Kinase- and Mitogen-Activated Protein Kinase-Dependent Mechanisms J. Immunol., November 1, 1998; 161(9): 5000 - 5007. [Abstract] [Full Text] [PDF]
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D. L. Mann and F. G. Spinale Activation of Matrix Metalloproteinases in the Failing Human Heart : Breaking the Tie That Binds Circulation, October 27, 1998; 98(17): 1699 - 1702. [Full Text] [PDF]
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Y. Y. Li, A. M. Feldman, Y. Sun, and C. F. McTiernan Differential Expression of Tissue Inhibitors of Metalloproteinases in the Failing Human Heart Circulation, October 27, 1998; 98(17): 1728 - 1734. [Abstract] [Full Text] [PDF]
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E. J. Topol and P. W. Serruys Frontiers in Interventional Cardiology Circulation, October 27, 1998; 98(17): 1802 - 1820. [Full Text] [PDF]
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Y. Itoh, A. Ito, K. Iwata, K. Tanzawa, Y. Mori, and H. Nagase Plasma Membrane-bound Tissue Inhibitor of Metalloproteinases (TIMP)-2 Specifically Inhibits Matrix Metalloproteinase 2 (Gelatinase A) Activated on the Cell Surface J. Biol. Chem., September 18, 1998; 273(38): 24360 - 24367. [Abstract] [Full Text] [PDF]
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F. W. Muskett, T. A. Frenkiel, J. Feeney, R. B. Freedman, M. D. Carr, and R. A. Williamson High Resolution Structure of the N-terminal Domain of Tissue Inhibitor of Metalloproteinases-2 and Characterization of Its Interaction Site with Matrix Metalloproteinase-3 J. Biol. Chem., August 21, 1998; 273(34): 21736 - 21743. [Abstract] [Full Text] [PDF]
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R. P. Fabunmi, G. K. Sukhova, S. Sugiyama, and P. Libby Expression of Tissue Inhibitor of Metalloproteinases-3 in Human Atheroma and Regulation in Lesion-Associated Cells : A Potential Protective Mechanism in Plaque Stability Circ. Res., August 10, 1998; 83(3): 270 - 278. [Abstract] [Full Text] [PDF]
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K. Lampert, U. Machein, M. R. Machein, W. Conca, H. H. Peter, and B. Volk Expression of Matrix Metalloproteinases and Their Tissue Inhibitors in Human Brain Tumors Am. J. Pathol., August 1, 1998; 153(2): 429 - 437. [Abstract] [Full Text] [PDF]
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W. B. Nothnick, P. D. Soloway, and T. E. Curry, Jr. Pattern of Messenger Ribonucleic Acid Expression of Tissue Inhibitors of Metalloproteinases (TIMPs) during Testicular Maturation in Male Mice Lacking a Functional TIMP-1 Gene Biol Reprod, August 1, 1998; 59(2): 364 - 370. [Abstract] [Full Text]
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K. P. Langton, M. D. Barker, and N. McKie Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation J. Biol. Chem., July 3, 1998; 273(27): 16778 - 16781. [Abstract] [Full Text] [PDF]
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P. Silacci, J.-M. Dayer, A. Desgeorges, R. Peter, C. Manueddu, and P.-A. Guerne Interleukin (IL)-6 and Its Soluble Receptor Induce TIMP-1 Expression in Synoviocytes and Chondrocytes, and Block IL-1-induced Collagenolytic Activity J. Biol. Chem., May 29, 1998; 273(22): 13625 - 13629. [Abstract] [Full Text] [PDF]
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 K. Airola, M. Ahonen, N. Johansson, P. Heikkilä, J. Kere, V.-M. Kähäri, and U. K. Saarialho–Kere Human TIMP-3 Is Expressed During Fetal Development, Hair Growth Cycle, and Cancer Progression J. Histochem. Cytochem., April 1, 1998; 46(4): 437 - 448. [Abstract] [Full Text]
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 L. C. Bailey Jr., D. B. Searls, and G. C. Overton Analysis of EST-Driven Gene Annotation in Human Genomic Sequence Genome Res., April 1, 1998; 8(4): 362 - 376. [Abstract] [Full Text]
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F. M. Botelho, D. R. Edwards, and C. D. Richards Oncostatin M Stimulates c-Fos to Bind a Transcriptionally Responsive AP-1 Element within the Tissue Inhibitor of Metalloproteinase-1 Promoter J. Biol. Chem., February 27, 1998; 273(9): 5211 - 5218. [Abstract] [Full Text] [PDF]
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 W. Zhao, H Li, K Yamashita, X. Guo, T Hoshino, S Yoshida, T Shinya, and T Hayakawa Cell cycle-associated accumulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) in the nuclei of human gingival fibroblasts J. Cell Sci., January 5, 1998; 111(9): 1147 - 1153. [Abstract] [PDF]
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