Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane-type 3 matrix metalloproteinase (MT3-MMP) is a novel MT-MMP which has a transmembrane domain at the C terminus, and mediates activation of pro-gelatinase A, just as does MT1-MMP. Previously, we reported that MT1-MMP was expressed on microglial cells only in the white matter [Yamada T, Yoshiyama Y, Sato H, Seiki M, Shinagawa A, Takahashi M (1995) Acta Neuropathol 90:421-424]. In the present study of both non-neurological and Alzheimer brain tissues, we examined the localization of MT3-MMP by immunohistochemistry. Anti-MT3-MMP antibodies gave positive staining of microglial cells in all brain tissues. Positively stained microglia were found not only in the white matter but also in the gray matter. Reverse transcriptase-polymerase chain reaction for MT3-MMP mRNA showed the same amount of expression in gray and white matters, while that for gelatinase A and MT1-MMP mRNA expressed much higher in the white matter than in the gray matter. These results suggest that MT3-MMP may play a role on microglial cells, although its role may be different from MT1-MMP in the brain.
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PMID:Expression of the membrane-type 3 matrix metalloproteinase (MT3-MMP) in human brain tissues. 979 98

The two matrix metalloproteinases (MMPs) Mr 72,000 type IV collagenase (MMP-2, gelatinase A) and Mr 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a Mr 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.
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PMID:Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes. 1035 46

It is known that the migration of melanocyte precursors (melanoblasts) from the outer root sheath of hair follicles into clinically depigmented epidermis is crucial to the repigmentation of vitiliginous skin treated with photochemotherapy (PUVA), but such migratory cells must penetrate extracellular matrix tissue barriers in vivo. To test the hypothesis that matrix metalloproteinases (MMPs) are required for this process, we determined whether cultured melb-a cells, an immortal line of melanoblasts isolated from neonatal mouse epidermis, express and secrete MMPs and whether a synthetic metalloproteinase inhibitor, GM6001 (Galardin), inhibits their migratory behavior in vitro. Reverse transcriptase-polymerase chain reaction and Western blotting were used to determine the patterns of MMP expression by melanoblasts at the mRNA and protein levels, respectively. The proteolytic activities of MMPs secreted into the culture medium were assessed by gelatin zymography. The capacity of melanoblasts to migrate on fibronectin, laminin or laminin-5 substrates was estimated using Transwell migration assays. The results show that MMP2, MMP9 and MT1-MMP transcripts are expressed by these melanoblasts, but only MMP2 is secreted and activated in the extracellular environment. Although the therapeutic efficacy of PUVA in stimulating repigmentation of vitiliginous skin might derive from direct effects of UVA and/or 8-methoxypsoralen (8MOP), recent studies have shown that keratinocyte-derived factors induced by ultraviolet radiation, especially alpha-melanocyte stimulating hormone (alpha MSH), play a major role in regulating melanocyte function. Therefore, we also examined whether 8MOP and/or alphaMSH are involved in the up-regulation of MMP2 expression in melanoblasts. Western blotting and zymographic analyses revealed that MMP2 synthesis and secretion were induced by 8MOP and/or by alpha MSH. This induction of MMP2 resulted in significant increases of migration by melanoblasts on laminin or on laminin-5 substrates, while concomitant treatment with GM6001 blocked that induced migration. Taken together, these results suggest the importance of MMP2 in melanoblast migration and in the response to PUVA therapy.
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PMID:In vitro migration of melanoblasts requires matrix metalloproteinase-2: implications to vitiligo therapy by photochemotherapy. 1245 84

In contrast to adult cutaneous wounds, early fetal wounds heal scarlessly. Fetal rat skin transitions from scarless repair to healing, with scar formation between days 16.5 (E16) and 18.5 (E18) of gestation. Term gestation is 21.5 days. The composition of the extracellular matrix in fetal skin and wounds differs from that of the adult. Matrix metalloproteinases (MMPs) and their tissue-derived inhibitors (TIMPs) determine the architecture of the extracellular matrix. The authors hypothesized that differential expression of MMPs and TIMPs occurs during the ontogenetic transition to scar-forming repair in fetal skin and wounds. Full-thickness, excisional wounds (2 mm) were created on the dorsum of E16 (n = 42 fetuses) and E19 fetal rats (n = 42 fetuses). Wounds were harvested at 24, 48, and 72 hours. Nonwounded skin from littermates was also harvested as controls. Six E16 and E19 wounds were fixed 72 hours after injury, stained with hematoxylin and eosin, and examined by light microscopy. RNA was isolated from the remaining wounds and skin, and a reduced-cycle, primer-specific, reverse-transcriptase polymerase chain reaction was performed to semiquantitatively determine relative gene expression of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 and of TIMP-1, TIMP-2, and TIMP-3. Significance was determined by unpaired two-tailed t test (p < 0.05) and analysis of variance. In both E16 and E19 wounds, reepithelialization was complete by 72 hours. E16 wounds healed scarlessly, whereas E19 wounds healed with scar. During late gestation, skin expression of MMP-1 and MMP-14 (membrane type-1 MMP) doubled, whereas MMP-2 expression increased nearly 50-fold. Levels of MMP-7 and MMP-9 were unchanged in developing skin. As for the TIMPs, skin expression of TIMP-2 increased more than four-fold, whereas TIMP-1 and TIMP-3 expression was unchanged. In both scarless and scarring wounds, up-regulation of MMP-1 and MMP-9 occurred. However, the maximal increase in MMP-1 and MMP-9 expression occurred much more rapidly and was much greater in the scarless E16 wounds (28-fold versus 23-fold for MMP-1 and 18-fold versus nine-fold for MMP-9). Unchanged in scarless wounds, MMP-2 levels decreased more than three-fold in scarring wounds. MMP-14 (membrane type-1 MMP) expression increased three-fold in scarless wounds but was unchanged in scarring wounds. In contrast, TIMP-1 and TIMP-3 expression in E19 scarring wounds increased six-fold and four-fold, respectively. MMP-7 and TIMP-2 expression did not change in response to injury. E16 scarless wounds have greater MMP relative to TIMP expression than E19 scarring wounds. This favors extracellular matrix turnover, facilitates migration of fetal cells, and promotes scarless repair.
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PMID:Scarless fetal wounds are associated with an increased matrix metalloproteinase-to-tissue-derived inhibitor of metalloproteinase ratio. 1279 70

Liver regeneration depends on timely restoration of cellular mass while orchestrating structural matrix remodeling. Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) are known to regulate the extracellular matrix (ECM) turnover and, more recently, the processing of growth factors and cytokines. We have previously demonstrated that TIMP-1 inhibits preneoplastic hepatocyte proliferation by attenuating growth factor bioavailability. In the present study, we examined the role of TIMP-1 in de novo hepatocyte cell division during liver regeneration. Comprehensive real-time reverse-transcriptase polymerase chain reaction analyses of regenerating livers revealed significant inductions in the messenger RNA of TIMP-1, TIMP-3, TIMP-4, MMP-2, MMP-9, MMP-13, MMP-14, and MMP-24, while MMP-15 expression was significantly reduced. Induction of TIMP-1 occurred during the peak of hepatocyte DNA synthesis. Studies using genetically altered mice revealed that TIMP-1 loss of function accelerated hepatocyte cell cycle progression. This finding was demonstrated by earlier expression of cyclin D1, proliferating cell nuclear antigen, and phosphorylated histone H3, which mark the G(1)-S, S, and M phase, respectively. Conversely, TIMP-1 gain of function delayed cell cycle progression. MMP activity was increased in the absence of Timp-1. Examination of hepatocyte growth factor (HGF), and its receptor Met, both of which provide a mitogenic signal for hepatocyte division, showed increased HGF activity in Timp-1(-/-)-regenerating livers. HGF is released from the ECM and is proteolytically processed to its active form. Active HGF was elevated in Timp-1(-/-) mice, leading to increased immunostaining of phosphorylated Met as well as activation of a downstream effector, p38. In conclusion, TIMP-1 is a novel negative regulator of HGF activity during liver regeneration.
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PMID:Metalloproteinase inhibitor TIMP-1 affects hepatocyte cell cycle via HGF activation in murine liver regeneration. 1572 41

Tumor embolism occurs in 30 to 50% of all cases of cardiac myxoma, but the causes are still uncertain. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the extracellular matrix (ECM) and play a crucial role in plaque instability and aortic aneurysm development, in addition to cancer and heart failure. To determine whether MMP activity contributes to tumor embolism, we examined 27 left atrium-sided myxomas, 10 of which showed clinical signs of peripheral embolism. Immunohistochemistry (in all cases) and Western blotting, and in situ and in-gel zymography (in four embolic and six nonembolic consecutive tumors) demonstrated higher expression and activity of MT1-MMP, pro-MMP-2, and pro-MMP-9 in embolic myxomas, whereas pro-MMP-1, MMP-3, and TIMP-1 levels were similar to those of nonembolic tumors. Reverse transcriptase-polymerase chain reaction demonstrated that increased MMP activity was due, at least in part, to increased transcription and that TIMP-2 transcripts increased in embolic myxomas. In vitro, embolic tumor cells retained higher MT1-MMP and pro-MMP-2 levels in basal conditions and after stimulation with interleukin-1beta and interleukin-6. Increased MMP synthesis and release correlated with enhanced ECM degradation products containing glycosaminoglycan chains in embolic myxoma tissue. Our results strongly suggest that MMP overexpression may contribute to an excessive degradation of tumor ECM and increase the risk of embolism in cardiac myxomas.
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PMID:Increased expression and activity of matrix metalloproteinases characterize embolic cardiac myxomas. 1592 Jan 47

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and membrane-type matrix metalloproteinase 1 (MT1-MMP) are involved in colorectal cancer invasion and metastasis. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) inhibits MMP-2, MMP-9 and MT1-MMP. We examined the clinicopathological significance of the relative expression of these genes in patients with colorectal cancer, especially with regard to metastasis. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal carcinoma. MMP-2, MMP-9, MT1-MMP, RECK and beta-actin mRNA of cancer tissue and adjacent normal mucosa were measured by quantitative real-time reverse-transcriptase polymerase chain reaction. MT1-MMP gene expression was higher in cancer tissue than in adjacent normal mucosa. In contrast, MMP-2, MMP-9 and RECK gene expression levels were lower in cancer tissue than in adjacent normal mucosa. As for the relationship between the gene expression and clinicopathological factors, MMP-2 expression correlated with the depth of invasion, venous invasion and liver metastasis; MMP-9 and RECK expression correlated with venous invasion. There were positive correlations among the gene expression levels of MMP-2, MMP-9 and RECK. MMP-2 gene expression was considered a useful predictor of liver metastasis from colorectal cancer.
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PMID:Clinicopathological significance of the gene expression of matrix metalloproteinases and reversion-inducing cysteine-rich protein with Kazal motifs in patients with colorectal cancer: MMP-2 gene expression is a useful predictor of liver metastasis from colorectal cancer. 1842 89