Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-five surgical specimens of malignant human prostate, 3 lymph nodes with metastatic prostate carcinoma, 11 normal human prostates, as well as 3 human prostate cell lines (DU-145, PC3 and LNCaP) were examined for the expression of the human matrix metalloproteinase-7 gene (MMP-7) from the human collagenase family (originally called PUMP-1 for putative metalloproteinase-1) [Quantin et al. (1989) Biochemistry 28:5327-5334; Muller et al. (1988) Biochem J 253:187-192; Matrisian and Bowden (1990) Semin Cancer Biol 1:107-115]. Northern blots were prepared using total RNA extracted from 18 prostate adenocarcinomas, 2 lymph nodes with metastatic prostate carcinoma and 11 normal human prostates. When the northern blots were hybridized with a 32P-labeled MMP-7 cDNA probe, a 1.2-kb mRNA was detected in 14 out of 18 prostate adenocarcinomas, 1 out of 2 metastatic lymph nodes, and 3 out of 11 normal prostates. The 3 human prostate cell lines did not show any evidence of the MMP-7 transcript. In situ hybridization was conducted to localize the MMP-7 mRNA to individual cells using a 35S-labeled MMP-7 cRNA. In situ hybridization was carried out on snap-frozen tissue sections of 7 prostate adenocarcinomas and 3 lymph nodes containing metastatic prostate adenocarcinoma using the same tissues previously probed by northern analysis as well as new samples. In situ hybridization revealed that the MMP-7 gene was expressed in the epithelial cells of primary prostate adenocarcinoma as well as in invasive and metastatic cells. MMP-7 expression was also seen focally in some dysplastic glands but not in stroma. Additional northern blot analysis was performed using probes to human type-IV collagenase, type-I collagenase and stromelysin I in human prostate adenocarcinoma as well as normal prostate tissue. Our results indicated that 6 out of 10 adenocarcinoma samples and none of the 4 normal samples were positive for type-IV collagenase transcripts. Tissue samples were also examined for the expression of type-I collagenase (9 adenocarcinomas and 4 normal) and stromelysin I (13 adenocarcinomas) by northern analysis. None of the tissues was found to express the transcripts of interest at detectable levels. These data suggest that certain metalloproteinases are present in prostatic adenocarcinoma and may play a role in invasion and metastasis.
J Cancer Res Clin Oncol 1991
PMID:Expression of metalloproteinase genes in human prostate cancer. 184 60

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over-expressed in a simultaneous or co-ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady-state levels of mRNA coding for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue-specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non-metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15- to 20-fold, while TIMP transcripts were decreased 3-fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5-3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
Int J Cancer 1991 Jun 19
PMID:Constitutive expression and secretion of proteases in non-metastatic SP1 mammary carcinoma cells and its metastatic sublines. 204

We have reported that down-modulation of tissue inhibitor of metalloproteinases (TIMP) by means of antisense RNA converts non-tumorigenic Swiss 3T3 cells into malignant cells capable of forming metastasizing tumors in nude mice [Science 243:947 (1989)]. We now describe changes in the expression of specific genes associated with tumor progression of two lines down-modulated with TIMP, LA1 and LA7. Six independent variant cell lines, generated from different primary tumors produced by LA1 and LA7, lacked (like LA1 and LA7) many characteristics of typical transformed cells. However, their tumorigenicity in nude mice was enhanced; tumors appeared with a shorter lag (1-3 weeks versus 8-10 weeks for the parental clones, LA1 and LA7) and grew very rapidly. Increases, substantial in some cases, in the expression of a cysteine proteinase, cathepsin L, and metalloproteinases homologous to rat transin (stromelysin) and transin-2 were characteristic of these variant clones. The mRNA levels encoding the transformation-associated secreted phosphoprotein (osteopontin) and the calcium-binding protein calcyclin were also augmented. No evidence for gene amplification was found, and we did not detect any change in the mRNA levels of the proto-oncogenes that were examined. These novel cell lines represent a new paradigm for the transformed cell. Our data suggest that a reduction in TIMP secretion enhances the cell's oncogenic capacity by altering the extracellular environment in a way conducive to further changes in gene expression necessary for tumor progression.
J Cancer Res Clin Oncol 1991
PMID:Increased proteinase expression during tumor progression of cell lines down-modulated for TIMP levels: a new transformation paradigm? [corrected]. 206 53

There are several characteristics of stromelysin that suggest that expression of this enzyme may play an important role in tumor invasion and metastasis; the stromelysin gene is expressed in response to stimulation by oncogenes and tumor promoters, and the protein product of this gene is a metalloproteinase capable of degrading multiple components of the extracellular matrix. Experimental evidence to support this hypothesis has been derived from several animal model systems, in which a positive correlation has been observed between stromelysin expression and tumor progression and metastasis. In addition, in vivo experiments in which the levels of TIMP, the tissue inhibitor of metalloproteinases, were altered also strongly suggest a causal role for metalloproteinases in tumor metastases. The expression of active stromelysin in tumor cells requires the fulfillment of several criteria, and this multistep process is reminiscent of the molecular events that are currently understood to contribute to tumor progression and carcinogenesis. Expression of stromelysin mRNA requires both a stimulus, a step which may correspond to the activation of an oncogene in multistep carcinogenesis, as well as the lifting of transcriptional repression, which may correspond to the loss of tumor suppressor function. Both positive and negative modulation of stromelysin transcription appear to utilize pathways that involve the protooncogenes c-fos and/or c-jun. The expression of active stromelysin enzyme also requires conversion of the proenzyme to an active form, and a proper balance between the expression of inhibitors and the levels of active enzyme. The multiple levels of stromelysin regulation support the concept of multistep carcinogenesis and may provide a tool for further understanding of the molecular nature of the events that lead to tumor progression, invasion, and metastasis.
Cancer Metastasis Rev 1990 Dec
PMID:Stromelysin in tumor progression and metastasis. 209 83

Transin is an oncogene-inducible protein which has been shown to be the rat homologue of an extracellular matrix-degrading metalloproteinase known as stromelysin. The activity of transin/stromelysin is regulated at several levels: (1) at the transcriptional level, it is positively regulated by oncogenes, tumor promoters, and certain growth factors, and is negatively regulated by several agents including glucocorticoids and transforming growth factor-beta; (2) the protease activity is produced by processing of an inactive precursor form to an active enzyme; and (3) total protease activity is modulated by activity of tissue inhibitors of metalloproteinases (TIMPs). The association of transin/stromelysin expression with tumor progression suggests that it plays an important role in cancer.
Semin Cancer Biol 1990 Apr
PMID:Stromelysin/transin and tumor progression. 210 88

The invasion and metastasis of cancer cells is a complex multistep process involving attachment of tumor cells to the basement membrane, proteolysis of the local connective tissue stroma, and migration through the proteolyzed stroma. Recent evidence implicates metalloproteinases such as type IV collagenase and transin/stromelysin in the proteolytic aspects of this process. Type IV collagenase activity is modulated by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). Immunohistochemical and biochemical studies of several human tumors show correlations between invasive potential and type IV collagenase activity.
Semin Cancer Biol 1990 Apr
PMID:Metalloproteinases and cancer invasion. 210 92

We examined the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on EGF receptor (EGFR) phosphorylation and the expression of mRNAs for oncogenes, growth factors, their receptors and metalloproteinase genes by MKN-28 gastric carcinoma cells which express EGF, TGF-alpha and EGFR genes. Both EGF and TGF-alpha stimulated EGFR phosphorylation, EGF and TGF-alpha induced FOS, MYC and ERBB-2 oncogene expression. Interestingly, EGF increased the expression of mRNAs for TGF-alpha and EGFR. On the other hand, TGF-alpha increased TGF-alpha mRNA but decreased the expression of mRNAs for EGFR and TGF-beta. Furthermore, mRNAs for interstitial collagenase, stromelysin and procollagen type I genes were also enhanced after treatment with EGF and TGF-alpha. These results indicate that EGF and TGF-alpha successively evoke cascade phenomena which favor tumor progression, invasion and extracellular matrix formation, acting as autocrine growth regulators for gastric carcinomas.
Jpn J Cancer Res 1990 Aug
PMID:Induction of growth factor-receptor and metalloproteinase genes by epidermal growth factor and/or transforming growth factor-alpha in human gastric carcinoma cell line MKN-28. 216 68

It has been proposed that tumor progression is a selective process and that only a minority of tumor cells survive this selection because they possess the phenotypic traits necessary for metastasis and organ colonization. Both proteases and extracellular matrix proteins have been implicated in invasion and metastasis formation. To examine the nature of the selection process, we transformed 10T1/2 fibroblasts with T24 H-ras and the neoR gene and selected a clonal line expressing the mutant ras gene. After i.v. injection of this line into syngeneic C3H/HeN mice, tumor cells were recovered from lungs by enzymatic treatment and selective outgrowth in G418. Less than one of 10(3) cells survived in the lung 30 min after inoculation, and these exhibited a unique phenotype. This was characterized by a propensity to lodge in the lung on reinjection; markedly enhanced mRNA levels of procollagen alpha 2(I), procollagen alpha 1(III), and fibronectin; and decreased levels of laminin, major excreted protein (procathepsin L), transin, and H-ras. Between 1 and 9 days after tumor injection, the phenotype of the cells surviving in the lung changed dramatically and exhibited a pattern of gene expression with increased protease and low matrix protein mRNA levels. This coincided with a 26-fold increase in the ability to colonize lungs on i.v. injection. Both the phenotype characterized by its propensity to arrest in the lung and that showing enhanced metastatic ability were unstable on prolonged in vitro culture. We hypothesize that two selection events have occurred. The first is for lung arrest and implantation of variants of the injected tumor with high matrix protein and low protease levels. A second selection then occurs for tumor cells that carry a favorable phenotype for invasion and proliferation which is associated with low matrix protein and high protease gene expression. These two phenotypes are represented within a clonal population of recently transformed tumor cells.
Cancer Res 1990 Jul 01
PMID:Transient alterations in the expression of protease and extracellular matrix genes during metastatic lung colonization by H-ras-transformed 10T1/2 fibroblasts. 219 71

A metalloproteinase with Mr 29,000 was purified to homogeneity as a latent proenzyme from the conditioned medium of a human rectal carcinoma cell line CaR-1. This enzyme hydrolyzed casein more potently than gelatin embedded in polyacrylamide gels in zymography assay. Calcium ion was essential for the activity. It exerted the maximum activity at pH 7-9. Its activity was stimulated by organomercurials, such as p-amino-phenyl mercuric acetate and p-chloromercuric benzoic acid, and was inhibited by 1,10-phenanthroline but was hardly affected by diisopropyl fluorophosphate and pepstatin. When the purified proenzyme was activated by the organomercurials, it effectively hydrolyzed fibronectin, laminin, type IV basement membrane collagen, and several types of gelatins but not interstitial type I and III collagens. The treatment of the purified proenzyme with p-aminophenyl mercuric acetate or trypsin formed an active peptide with Mr 20,000. The structural analysis indicated that it was most likely identical to putative metalloproteinase-1, the complementary DNA of which had been cloned from human tumor mRNAs capable of hybridizing to a rat transin complementary DNA. Based on the fact that this enzyme is secreted extracellularly and degrades the matrix proteins, we propose the name "matrin" for this newly identified enzyme.
Cancer Res 1990 Dec 15
PMID:Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line. 225 19

The treatment of HL-60 promyelocytic leukemia cells with phorbol esters (12-O-tetradecanoylphorbol-13-acetate) results in the appearance of cell substrate adhesion and the release of a Mr 94,000 gelatin-degrading metalloprotease. The appearance of the metalloprotease in the culture medium directly correlates with the timing and extent of cell substrate adhesion over a 24-h period. Anti-Mr 94,000 metalloprotease blocking antibodies were unable to interfere with the HL-60 cell substrate adhesion induced by 12-O-tetradecanoylphorbol-13-acetate, although they were able to specifically remove the Mr 94,000 gelatin-degrading activity from either HL-60 or U-937 cell-conditioned medium. A purified metalloprotease preparation was found to be predominantly latent and activated by organomercurials, acid treatment (pH 2 to 3.6), or 8 M urea. The activating effect of the latter two denaturing treatments suggests that conformational changes may be the common activating mechanism. The different treatments also caused the appearance of lower molecular weight gelatin-degrading bands (in gelatin zymogram gels) in a manner consistent with the autocatalytic cleavage that occurs with other collagnase proenzymes during activation. Edman degradation of a cyanogen bromide fragment from the Mr 94,000 metalloprotease provided the amino acid sequence [PR(C)GVPD] which is present in type I collagenase, stromelysin, and transin proenzyme sequences and partially conserved (V----N substitution) in the type IV collagenase proenzyme. This sequence has been reported to be important in the maintenance of the latent state of the transin proenzyme (R. Sanchez-Lopez et al., J. Biol. Chem., 263: 1892-11899, 1988) and is a sequence unique to collagenase proenzymes. The N-terminal sequence of the Mr 94,000 metalloprotease (AP-QDQST) is unique and distinct from other collagenases. Thus, the Mr 94,000 metalloprotease from HL-60 cells appears to be a distinct and new member of the collagenase family of proteases.
Cancer Res 1990 Feb 15
PMID:A latent Mr 94,000 gelatin-degrading metalloprotease induced during differentiation of HL-60 promyelocytic leukemia cells: a member of the collagenase family of enzymes. 229 60


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