Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex steroids are important regulators of bone cell function and osteoblast-derived matrix metalloproteinases (MMPs) are key mediators of bone resorption during the initial stage of osteoid removal prior to osteoclast attachment. To investigate the mechanism of bone loss following estrogen deficiency, we examined the effects of estrogen on osteoblast synthesis of MMPs and tissue inhibitor of metalloproteinases (TIMPs). Immunolocalization in mouse bone samples ex vivo and primary mouse osteoblast (MOB) cultures was used to document the synthesis of mouse interstitial collagenase (MMP-13), stromelysin-1 (MMP-3), gelatinase-A (MMP-2), and gelatinase-B (MMP-9). Endosteal bone lining cells from distal femoral head and lumbar vertebral body showed an increase in the pattern of synthesis of stromelysin-1 following ovariectomy, compared with sham-operated controls; the synthesis of other MMPs was unaffected. The expression of all classes of MMPs and TIMP-1 and TIMP-2 by MOB in culture was demonstrated by reverse transcriptase-polymerase chain reaction. Following the withdrawal of 17beta-estradiol, MOB cultures showed a significant increase in the number of cells synthesizing stromelysin-1; this effect was enhanced by stimulation with either interleukin-1 or interleukin-6. Northern blot analysis showed only a slight increase in stromelysin-1 mRNA message following the withdrawal of 17beta-estradiol. Our data show an unexpected up-regulation of stromelysin-1 synthesis by osteoblasts both in vivo and in vitro following estrogen withdrawal. Although this effect was not reflected in a significant change in stromelysin-1 mRNA expression in vitro, there is evidence to suggest a role for this enzyme in the early stages of bone loss during the pathogenesis of osteoporosis.
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PMID:Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient mouse osteoblasts in vivo and in vitro. 1057 88

Hereditary gingival fibromatosis (HGF) is characterized by an excess accumulation of extracellular matrix (ECM) resulting in a generalized and fibrotic enlargement of the gingiva. To investigate some of the regulatory features of this condition, gingival fibroblasts from normal gingiva (NG) and HGF were examined for the expression and production of matrix metalloproteinases (MMPs) and their inhibitors, tissue matrix metalloproteinases inhibitor (TIMPs). Our results, obtained from 2 different assays, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzymography, clearly demonstrated that the expression and production of MMP-1 and MMP-2 was significantly lower in fibroblasts from HGF than from NG. Interestingly, TIMP-1 and TIMP-2 expression from NG cells was shown to be slightly higher to those from HGF. Addition of antibodies against transforming growth factor-beta 1 (TGF-beta 1), which is produced in greater amounts by HGF fibroblasts, resulted in a slight increase in MMP-1 and a decrease in MMP-2 expression, whereas TIMP-1 and TIMP-2 expressions were unaffected. These patterns of expression and production suggest that enhanced TGF-beta 1 production reduce the proteolytic activities of HGF fibroblasts, which favor the accumulation of ECM.
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PMID:Alteration in expression of MMP-1 and MMP-2 but not TIMP-1 and TIMP-2 in hereditary gingival fibromatosis is mediated by TGF-beta 1 autocrine stimulation. 1069 2

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are important in any process of tissue remodeling. However, there is no report evaluating their expression in cardiac allografts in human or non-human primates. Heterotopic cardiac transplantation was performed on Japanese monkeys. Subjects were treated with chimeric anti-human lymphocyte function-associated antigen-1 monoclonal antibody for 2 weeks. Heart grafts were harvested at days 1-95 (n = 7). Native monkey hearts were used as controls (n = 2). We examined expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 using immunohistochemistry and in situ reverse transcriptase polymerase chain reaction (RT-PCR). In the myocardium, the expression of MMP-2 was increased in the spindle-shaped cells of acutely rejected myocardial interstitium and prior to the presence of mononuclear cell infiltration at days 1-41. TIMP-1 and 2 expression was enhanced in association with the progression of fibrosis at days 40-95. In the coronary arteries of chronically rejected allografts, enhanced MMP and decreased TIMP expression was observed in both thickened intima and media at days 40-95. The medial MMP mRNA expression was observed before the development of intimal thickening occurred at days 7-28. MMPs are critical for the progression of acute and chronic rejection, and TIMP predominance plays important roles in fibrosis in association with acute rejection. Expression of MMPs and TIMPs is a sensitive indicator of acute and chronic cardiac rejection.
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PMID:Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosis in cardiac allografts of nonhuman primates. 1083 46

There is a growing body of evidence that implicates matrix metalloproteinases (MMPs) as major players in numerous diseased conditions. The articular cartilage degradation that is characteristic of rheumatoid arthritis (RA) is believed to be mediated by the collagenase subfamily of matrix metalloproteinases. The preference of collagenase-3 (CL-3) for collagen type II makes it a likely candidate in the turnover of articular cartilage and a potential target for drug development. In this study, RA synovial membrane tissue was shown to express CL-3 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and protein by immunohistochemistry. Fibroblasts isolated and cultured from RA synovial membrane tissue were induced to express CL-3 mRNA. CL-3 mRNA was detected after PMA treatment in 16 of the 18 RA synovial membrane fibroblast cell lines established for this study. These fibroblasts also expressed mRNA for collagenase-1 (CL-1, MMP-1), membrane type-1 matrix metalloproteinase, gelatinase A, gelatinase B, stromelysin-1, stromelysin-2, TIMP-1, and TIMP-2. They were further shown to express CL-1 mRNA constitutively and CL-3 mRNA only after stimulation with PMA, IL-1, TGF-beta1, TNF-alpha, or IL-6 with IL-6sR. These fibroblasts also expressed after induction both CL-1 and CL-3 at the protein level as determined by Western blot analyses and immunofluorescence.
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PMID:Induction of collagenase-3 (MMP-13) in rheumatoid arthritis synovial fibroblasts. 1104 Apr 55

Dietary modification, especially the consumption of larger amounts of fruits and vegetables can act to decrease the risk of a variety of human cancers. Quercetin, a bioflavonoid widely distributed in fruits and vegetables has been shown to have a chemoprotective role in cancer, through complex effects on signal transduction involved in cell proliferation and angiogenesis. In this study we examined the effects of dietary supplementation of quercetin (30 mg per day) incorporated into a black currant drink. Healthy male subjects aged between 33 and 64 years (mean=47.1 years) received either quercetin or placebo for 14 days. Blood samples were taken at baseline and upon completion of the study and analysed for full blood count, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of matrix metalloproteinse-1 and -2 (TIMP-1 and -2) plasma levels using ELISA techniques. RNA was extracted from the peripheral blood lymphocytes and reverse transcriptase-polymerase chain reaction (RT-PCR) carried out for MMP-2 and TIMP-1, TIMP-2 gene expression determination. Supplementation of the diet with quercetin did not alter the MMP-2 or TIMP-2 gene transcription or plasma protein levels of the healthy subjects in this study. The TIMP-1 gene transcription and plasma protein levels (311+/-70 ng/ml at baseline to 183+/-35 ng/ml post-supplementation, P<0.05) of the subjects in this study were, however, significantly decreased following quercetin supplementation. This is an interesting result, as there is some controversy over the functions of TIMP-1 in tumour progression. In certain model systems, artificially increased TIMP-1 levels prevent or decrease tumour growth. However, in other studies high levels of TIMP-1 have been correlated with aggressive disease and poor prognosis in patients with certain malignancies. This study has outlined a potential role for the anti-tumour promoter quercetin as a dietary mediator of the carcinogenic cascade.
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PMID:Dietary supplementation with the anti-tumour promoter quercetin: its effects on matrix metalloproteinase gene regulation. 1150 19

Altered expression of matrix metalloproteases (MMPs) and their inhibitors, the tissue inhibitors of matrix metalloproteases (TIMPs), has been demonstrated in various tumour tissues. mRNA expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, MMP-12, MMP-14 and TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 30 renal cell carcinomas (RCC), as well as in the surrounding tissues. Expression of the MMPs was significantly stronger in the carcinomas than in non-malignant tissues. High levels were demonstrated particularly in clear cell RCCs (CC-RCC). Except for MMP-1, MMP expression in the papillary RCCs (P-RCC) was, for most MMPs, significantly lower. Expression of the TIMPs in malignant cells of both subtypes was weak, with the exception of TIMP-4 which was strongly expressed in the P-RCCs and downregulated in the CC-RCCs. The latter was correlated with chromosomal loss of 3p, harbouring the TIMP-4 gene locus. In conclusion, deregulated expression of the MMPs and TIMPs in RCCs differs according to histology, grade, size and cytogenetic characteristics, suggesting that MMP and TIMP expression patterns play an important role for the typical histomorphological features of RCC subtypes and their respective biological behaviour.
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PMID:mRNA expression of matrix metalloproteases and their inhibitors differs in subtypes of renal cell carcinomas. 1157 37

A cDNA encoding a putative tissue inhibitor of metalloprotease was cloned from an Ancylostoma caninum adult hookworm cDNA library by immunoscreening with anti-hookworm secretory products antiserum. Ac-TMP (A. caninum tissue inhibitor of metalloproteinase) is encoded by a 480-bp mRNA with a predicted open reading frame of 140 amino acids (molecular weight, 16,100 Da) that contains one potential N-linked glycosylation site and an N-terminal Cys-X-Cys consensus sequence. The open reading frame corresponds to a putative hookworm tissue inhibitor of metalloproteases (TIMP) with 33% identity and 50% similarity to the N-terminal domain of human TIMP-2. Analysis by reverse transcriptase-polymerase chain reaction indicates that transcription of Ac-tmp is restricted to the adult stage. The protein was isolated from A. caninum adult secretory products by reverse-phase high-performance liquid chromatography and identified as one of the most abundant proteins released by the parasite. To our knowledge, this is the first description of a TIMP from a parasitic invertebrate.
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PMID:Molecular cloning and purification of Ac-TMP, a developmentally regulated putative tissue inhibitor of metalloprotease released in relative abundance by adult Ancylostoma hookworms. 1213 14

In mammals, the gene Sry initiates signaling pathways triggering the differentiation of a testis from a sexually indifferent gonad. Assuming that these morphogenetic events may alter the proteolytic balance, the expression of matrix metalloproteinases (MMPs) and inhibitors (TIMPs) was investigated in gonads from 11.5 days postcoitum (dpc) onward, when testicular organogenesis occurs. Whereas selective MMPs and TIMPs (1-3) were detected in undifferentiated gonads (11.5 dpc) and in neonatal testes, a single TIMP (TIMP-1) was expressed in a sexually dimorphic manner from 12.5 dpc onward (i.e., after overt male gonad differentiation), demonstrated by using a semiquantitative reverse transcriptase-polymerase chain reaction and a Western blot analysis. To gain insight into the role of TIMP-1, the expression of gelatinases (mRNA levels and enzyme activity) was monitored. However, no sex differences could be evidenced, indicating that TIMP-1 was not inhibiting this class of MMPs during testis organogenesis. Apart from being an inhibitor of MMPs, TIMP-1 is known to display growth promoting activities. Of interest, testicular TIMP-1 (but not TIMP-2) levels were further enhanced up to 2 weeks of age, consistent with a role in the early postnatal testicular growth. We, therefore, established an organotypic culture system in which seminiferous cords may differentiate de novo and grow, depending on culture conditions. In that system and mimicking the in vivo situation, TIMP-1 immunolocalized strongly within the male gonadal territory and weakly in female gonads, in which no organization was evident. Experiments are now under way to determine to what extent TIMP-1 is a morphogenic gene involved in seminiferous cord formation and development.
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PMID:Differential expression of tissue inhibitor of metalloproteinases type 1 (TIMP-1) during mouse gonad development. 1281 21

Osteogenic properties of bone cells are a key parameter governing osseointegration of implant devices. In this context, osteoblasts have a central role via extracellular matrix synthesis and remodeling that they regulate through different protease activity. In this study, we have analyzed the expression of two matrix metalloproteinases (MMPs): MMP-2 (72 kDa) and MMP-9 (92 kDa) and their specific tissue inhibitors TIMP-1 and TIMP-2 in primary human osteoblastic cells. The effect of titanium, zirconia, and alumina ceramics on the synthesis of these proteases was assessed using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and zymographic analysis. Our results showed that osteoblasts express MMP-2 and -9 mRNA. Furthermore, MMP-2 mRNA expression was decreased by titanium and increased by alumina whereas zirconia did not have any significant effect. Conversely, MMP-9 mRNA expression was stimulated by titanium but decreased with zirconia, whereas alumina induced no significant changes. Zymographic analysis has evidenced pro-MMP-2 gelatinolytic activity in all cell populations with time-dependent increase profile; pro-MMP-9, however, was not detected. Enzyme-linked immunosorbent assay data confirmed the production of MMP-2 and very low levels of MMP-9. In addition, TIMP-1 was secreted in 24-h-cultured cells and increased to maximal level at 48-72 h whereas TIMP-2 levels were very low. The interactions between human osteoblasts and the studied biomaterials altered both MMP-2, -9 and TIMP-1expression indicating that biomaterials may influence osseointegration and bone remodeling.
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PMID:Matrix metalloproteinases MMP-2, -9 and tissue inhibitors TIMP-1, -2 expression and secretion by primary human osteoblast cells in response to titanium, zirconia, and alumina ceramics. 1466 Dec 56

In malignant tumors the balance of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) is disturbed. Radical oxygen species (ROS) and hydrogen peroxide potentially influence this balance. Therefore, we analyzed the balance of MMP and TIMP in renal cell carcinoma (RCC) specimens and cell lines. In RCC specimens MMP-2, MMP-9, TIMP-1, and TIMP-2 were immunohistochemically detected. Tumor-associated macrophages (TAM) as a potential source of ROS were characterized with an anti-CD68 antibody. Three RCC cell lines were treated with sublethal concentrations of hydrogen peroxide to simulate the effects of radical oxygen species. MMP-2 and MMP-9 protein expression was measured by zymography. mRNA expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 was assessed by quantitative reverse transcriptase polymerase chain reaction. Tumor cell-derived reactive oxygen species were measured by FACS analysis and dihydrorhodamine 123 oxidation. In RCCs the MMP and TIMP expression profile was variable. The balance between MMP and TIMP was shifted towards MMP in comparison to matched normal controls. TAM were localized in a close vicinity to MMP expresssing tumor cells. As in RCC specimens, the expression of MMP and TIMP in the analyzed RCC cell lines varied. Hydrogen peroxide induced MMP-2 and -9 mRNA and protein expression, whereas TIMP-1 and TIMP-2 mRNA levels remained unaffected in cell lines. Thus, the ratio between MMP and TIMP was shifted towards MMP. Tumor cells did not increase the production of reactive oxygen species stimulation with phorbol ester or hydrogen peroxide. In RCC the balance between MMP and TIMP is disturbed. Oxidative stress potentially increases this imbalance. TAM might be one source of hydrogen peroxide thus supporting the invasive properties of RCCs.
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PMID:The balance between MMP-2/-9 and TIMP-1/-2 is shifted towards MMP in renal cell carcinomas and can be further disturbed by hydrogen peroxide. 1506 27


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