Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiation pneumonitis is a major complication of radiation therapy. However, the detailed cellular mechanisms have not been clearly defined. Based on the recognition that basement membrane disruption occurs in acute lung injury and that matrix metalloproteinase (MMP)-2 can degrade type IV collagen, one of the major components of the basement membrane, we hypothesized that ionizing radiation would modulate MMP-2 production in human lung epithelial cells. To evaluate this, the modulation of MMP-2 with irradiation was investigated in normal human bronchial epithelial cells as well as in A549 cells. We measured the activity of MMP-2 in the conditioned medium with zymography and the MMP-2 mRNA level with RT-PCR. Both of these cells constitutively expressed 72-kDa gelatinolytic activity, corresponding to MMP-2, and exposure to radiation increased this activity. Consistent with the data of zymography, ionizing radiation increased the level of MMP-2 mRNA. This radiation-induced increase in MMP-2 expression was mediated via p53 because the p53 antisense oligonucleotide abolished the increase in MMP-2 activity as well as the accumulation of p53 after irradiation in A549 cells. These results indicate that MMP-2 expression by human lung epithelial cells is involved in radiation-induced lung injury.
Am J Physiol Lung Cell Mol Physiol 2001 Jan
PMID:Ionizing radiation enhances matrix metalloproteinase-2 production in human lung epithelial cells. 1113 92

The involvement of leukotriene (LT) B(4) in the ovulatory process of the rat was investigated by the use of a LTB(4)-receptor antagonist (ZK158252 = L-ANT) administered either intrabursally in vivo or to the in-vitro perfused ovary. The in-vivo experiments revealed inhibition of human chorionic gonadotrophin (HCG)-induced ovulation by 500 micromol/l L-ANT (median 5.5, 25-75% range 1.0-6.0) compared with controls (median 9.0, range 6.25-13.5). In vitro, ovulation was induced by LH (0.2 microg/ml) + 3-isobutyl-1-methylxanthine (IBMX; 0.2 mmol/l). The ovary was perfused either for 20 h, to study ovulation rate, or for 10 h to examine ovarian concentrations of the ovulatory mediators matrix metalloproteinase (MMP)-2 and MMP-9, plasminogen activator (PA), prostaglandin (PG)E(2) and PGF(2 alpha). Addition of LH+IBMX resulted in a marked stimulation of steroid release and ovulations occurred in all ovaries (median 11.0, range 10.0-14.0). The L-ANT inhibited ovulation in a dose-dependent way (median 10.0, range 8.0-13.0 at 1 micromol/l; median 6.0, range 3.5-10.0 at 10 micromol/l; median 2.0, range 0.75-5.75 at 100 micromol/l). The intra-ovarian activity of PA was increased 1.5-fold by L-ANT (100 micromol/l), but the concentrations of PGE(2) and PGF(2 alpha) remained unaltered. While no changes in MMP-9 were observed, conversion from pro-MMP-2 to active MMP-2 was inhibited by L-ANT. These results suggest that activation of the LTB(4)-receptor within the ovary is involved in the ovulatory process and that the effects of LTB(4)-receptor activation are partly mediated via MMP-2.
Mol Hum Reprod 2001 Jan
PMID:Inhibition of ovulation in the rat by a leukotriene B(4) receptor antagonist. 1113 58

Polycystic ovarian syndrome (PCOS) involves follicular atresia, formation of multiple ovarian cysts and is frequently associated with a higher abortion rate. Follicular development, ovulation, formation of corpus luteum and its regression involve extensive tissue remodelling. Mammalian ovaries express a number of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP). We assessed the differences in production of MMP-2, MMP-9 and TIMP-1 by cultured luteinized granulosa cells from women with PCOS and normal ovulatory women after ovarian stimulation for IVF treatment. In follicular fluid from women with PCOS, levels of MMP-9 and MMP-2 were higher than the normal group, as was the basal production of these proteins by cultured cells. Basal production of TIMP-1 by cultured cells was not different between PCOS and normal groups. A time-dependent increase in the production of MMP-9 was observed in cells from both normal and PCOS women, although the increase was more pronounced in the latter. Thus the MMP-TIMP balance is shifted toward greater MMP activity in luteinized granulosa cells from women with PCOS.
Mol Hum Reprod 2001 Apr
PMID:The balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells: comparison between women with PCOS and normal ovulatory women. 1127 94

Cleft lip and palate syndromes are among the most common congenital malformations in humans. Mammalian palatogenesis is a complex process involving highly regulated interactions between epithelial and mesenchymal cells of the palate to permit correct positioning of the palatal shelves, the remodeling of the extracellular matrix (ECM), and subsequent fusion of the palatal shelves. Here we show that several matrix metalloproteinases (MMPs), including a cell membrane-associated MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were highly expressed by the medial edge epithelium (MEE). MMP-13 was expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A (MMP-2) was expressed by mesenchymal cells neighboring the MEE. Transforming growth factor (TGF)-beta3-deficient mice, which suffer from clefting of the secondary palate, showed complete absence of TIMP-2 in the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-beta3 in palatal fibroblasts. Finally, palatal shelves from prefusion wild-type mouse embryos cultured in the presence of a synthetic inhibitor of MMPs or excess of TIMP-2 failed to fuse and MEE cells did not transdifferentiate, phenocopying the defect of the TGF-beta3-deficient mice. Our observations indicate for the first time that the proteolytic degradation of the ECM by MMPs is a necessary step for palatal fusion.
Mol Biol Cell 2001 May
PMID:TGF-beta3-induced palatogenesis requires matrix metalloproteinases. 1135 35

Chronic estrogen treatment results in elevated levels of the gelatinase pro-MMP-9 in the pituitary of tumor-susceptible Fischer 344 rats. In contrast, pituitary pro-MMP-9 level is not increased by estrogen treatment in rats of the tumor-resistant BN strain nor in rats of an F(1) hybrid of these strains. The gelatinase MMP-2 is also detected in rat pituitary, but its level is not affected by either estrogen or rat genotype. In 124 estrogen-treated rats from a backcross of the F(1) hybrid to the F344 strain, the levels of both monomer and dimer forms of pro-MMP-9 correlate with the tumor phenotypes mass, total DNA, and hemoglobin content of the pituitary. In this backcross, the QTL Edpm5 (_e_strogen-_d_ependent _p_ituitary _m_ass on Chromosome 5) has a significant effect on MMP-9 levels, with inheritance of the BN allele of Edpm5 correlating with suppression of estrogen-dependent MMP-9 expression.
Mol Cell Endocrinol 2001 May 15
PMID:Suppression of estrogen-dependent MMP-9 expression by Edpm5, a genetic locus for pituitary tumor growth in rat. 1136 54

Scar formation following adult spinal cord (SC) hemisection is accompanied by important remodeling of the surrounding extracellular matrix (ECM). Since ECM molecules provide the substrate for axon growth, these changes in ECM composition are likely to influence the process of axonal regeneration. Here we investigated whether scar formation could be associated with the activation of matrix metalloproteinases (MMPs), a class of proteins implicated in ECM remodeling thought to favor axonal regeneration in the peripheral nervous system. Two members of the MMP family, MMP-2 and MMP-9, were found to be transiently upregulated in the SC wound. In situ fluorescent zymography revealed a MMP-related gelatinase activity (GA) in the wound, which was spatially and temporally correlated with scar formation. The GA formed a striking pattern of interwoven pathways along which neurites were seen to grow. These pathways corresponded to the distribution of other ECM molecules, which are known to have antagonistic effects on axonal regrowth. Our results suggest that neurite ingrowth into the wound may transiently benefit from this ECM remodeling and, in particular, from the upregulation of MMPs.
Mol Cell Neurosci 2001 Jun
PMID:MMP-related gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. 1141 85

Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are major regulators of tissue remodelling of the extracellular matrix (ECM) and may also be involved in the control of growth factor availability. We have investigated their production and localization in the developing human gonad during mid-gestation using zymographic techniques and immunohistochemistry. The secretion of MMP-2, MMP-9 and all four TIMP was demonstrated from both testis and ovary, with the predominant gelatinase produced by both being MMP-2. In the testis, MMP-1, MMP-2, MMP-9 and all TIMP family members were localized to the interstitium and to varying degrees within the tubules. MMP-9 and TIMP-4 were abundant in both Sertoli cells and gonocytes and MMP-1 and TIMP-1 were localized in particular to Sertoli cells. In the ovary, all TIMP and MMP-1, MMP-2 and MMP-9 were localized to the oogonium/oocyte cytoplasm with varying intensities and MMP-1, TIMP-2 and TIMP-3 were also detected in the ovarian stroma. This study demonstrates that MMP-1, MMP-2, MMP-9 and all TIMP family members are secreted by the developing ovary and testis and are localized to specific cell and tissue sites. MMP and TIMP are likely to play a role in ECM remodelling during gonadal development and also in the cell and matrix interactions that control a range of cellular functions.
Mol Hum Reprod 2001 Jul
PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human fetal testis and ovary. 1142 Mar 87

Invasion of malignant tumor cells is required for the formation of metastatic colonies. Uncontrolled expression of matrix metalloproteinase (MMP)-2 and MMP-9 is a critical part of the invasive potential of tumor cells and is affected by the balance between the enzymes and the inhibitors secreted by the cell. Here we analyzed the expression and activity of the two gelatinases (MMP-2 and MMP-9) as well as the expression levels of the tissue inhibitor of metalloproteinase (TIMP2)-, in different stages of carcinogenesis using mouse skin cell lines derived from tumors induced by chemical mutagens. Our results suggested that the expression of MMP-9 was implicated in the progression to spindle cell carcinomas in mouse keratinocytes. MMP-2 levels remained steady in all cell lines, whereas levels of TIMP-2 were increased in normal and spindle cells. The AP-1 DNA binding and transcriptional activity on the MMP-9 promoter were increased in the malignant cell lines, indicating the requirement of this binding site for its activation. The results of this study clearly suggested the important role of MMP-9, but not of MMP-2, in the metastatic properties of mouse keratinocytes.
Mol Carcinog 2001 Jun
PMID:Role of matrix metalloproteinase-9 in progression of mouse skin carcinogenesis. 1142 84

Dietary copper is required for normal function of >30 mammalian enzyme systems. Copper deficiency causes a number of cardiovascular defects as well as impaired immune cell function. Little is known regarding the effects of copper deficiency on acute inflammatory responses, but this topic is relevant because many members of the Western population receive less than the recommended dietary allowance of copper. In the current studies, we investigated the effects of dietary copper deficiency on acute lung injury induced by intrapulmonary deposition of IgG immune complexes. Weanling male Long-Evans rats were fed diets either adequate (5.6 microg/g) or deficient (0.3 microg/g) in copper. IgG immune complex lung injury was greatly increased in copper-deficient rats as determined by lung vascular leakage of albumin and histopathology. However, no change was observed in either the lung content of tumor necrosis factor-alpha or lung neutrophil accumulation. Lungs from copper-deficient rats had much higher levels of matrix metalloproteinase (MMP)-2 and MMP-9 than did copper-adequate control animals. This increased activity was not attributable to alveolar macrophages or neutrophils. These data suggest that the augmented lung injury caused by copper deficiency is due to increased pulmonary MMP-2 and MMP-9 activity and not a generalized amplification of the inflammatory response.
Am J Physiol Lung Cell Mol Physiol 2001 Aug
PMID:Augmented metalloproteinase activity and acute lung injury in copper-deficient rats. 1143 13

Alveolar epithelial cell (AEC) migration mediated by matrix metalloproteinases (MMPs) is required for lung development and repair after injury such as hyperoxia. Of specific interest in lung remodeling are the gelatinases, which are upregulated in AEC after hyperoxia. We correlated migration and gelatinase production in AEC cultured from fetal, adult, and hyperoxic rats. Fetal AEC (19-20 days) had higher MMP-2 and MMP-9 gelatinase expression than adult AEC, with fivefold higher MMP-9 activity, and were migratory through gelatin, responding to epidermal growth factor, keratinocyte growth factor, and fibroblast growth factor-10. MMP-2 and MMP-9 expression and migratory activity could be detected from the time of plating. In contrast, adult AEC migrated and expressed MMP-2 and MMP-9 proteins only after 48 h of culture. AEC from hyperoxic rats were significantly more migratory through gelatin than control adult AEC, with significantly higher MMP-9 activity. Inhibition of MMPs with doxycycline reduced the migration of AEC from hyperoxic rats to the level of control adult AEC. Fibronectin-cultured "hyperoxic" AEC acquired a temporary capacity for migration similar to the A549 lung cancer cell line, which is both highly migratory and invasive and is derived from the AEC type 2 lineage. These data suggest that MMP activity is associated with a migratory phenotype in fetal, hyperoxic, and transformed AEC in vitro, and we speculate that MMPs may play a key mechanistic role in AEC migration in vivo during lung development and repair.
Am J Physiol Lung Cell Mol Physiol 2001 Aug
PMID:Migration and gelatinases in cultured fetal, adult, and hyperoxic alveolar epithelial cells. 1143 18


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