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  • MMP-14 and TIMP-2 overexpression protects against hydroquinone-induced oxidant injury in RPE: implications for extracellular matrix turnover. 18055817

    To investigate whether overexpression of MMP-14 and/or TIMP-2 would overcome the effect of nonlethal oxidant injury with hydroquinone (HQ) on MMP-2 activity.Human MMP-14 and TIMP2 cDNA were cloned into a mammalian expression vector. Transient transfections were performed on human ARPE-19 cells. The cells were incubated 48 hours after transfection with a nonlethal dose of HQ for either 6 or 18 hours and then were collected for protein determination or RNA isolation. MMP-2 protein and activity were determined by Western blot and zymography. The extracellular matrix (ECM) components type I and type IV collagen and laminin were analyzed by Western blot analysis and real-time PCR.HQ for 6 hours modestly decreased MMP-2. MMP-2 recovered only after co-overexpression of MMP-14 and TIMP-2, but activity further decreased after HQ for 18 hours. MMP-14 or TIMP-2 overexpression alone contributed as much as the co-overexpression to the recovery of MMP-2 activity. MMP-2 protein seemed not to be altered. Type I collagen and laminin transcriptional levels remained unaffected, whereas type IV collagen transcripts decreased with HQ. Transfection with MMP-14 and/or TIMP-2 contributed to the return of type IV collagen levels to normal. On the other hand, type I and IV collagens and laminin protein accumulated after HQ treatment, an effect prevented by transfection.MMP-14 and TIMP2 contribute to the maintenance of adequate levels of MMP-2 activity in ARPE-19 cells after oxidant injury. In addition, changes in ECM components may result as a consequence of MMP-2 activity and may be relevant to the progression of dry AMD.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • [Effects of TIMP-2 gene transfection on biological behaviors of a metastatic human lung carcinoma cell line] 9772531

    OBJECTIVES: To explore the suppressive effects of tissue inhibitor of metalloproteinase 2 (TIMP-2) on malignant phenotype of human carcinoma cells and to evaluate its potential application in cancer gene therapy. METHODS: A man malian expression vector containing TIMP-2 cDNA was constructed and transfected into a metastatic human lung carcinoma cell line PG. In vitro and in vivo tests such as Northern blotting, immunohistochemistry as well as x enografting in nude mice experiment were used to analyse expression levels of TIMPs and MMPs, in vitro and in vivo behaviors of the tumor cells before and after the gene transfection. RESULTS: After transfection, the TIMP-2 mRNA expression was upregulated significantly. Changes, in some malignant phenotypes of the transfectants were seen. For instance, the abilities of in vitro invasion through Matrigel, colony formation on soft agar, tumorigenecity as well as spontaneous metastasis in nude mice were remarkably decreased. Immunohistochemical staining and in situ hybrydization showed that MMP2, MMP9, TIMP-1 and TIMP-2 were expressed by both tumor cells and stromal cells, with stronger staining at the site of tumor invasion. CONCLUSION: Up-regulation of TIMP-2 in tumor cells could suppress their expression of malignant phenotype and could be used for cancer therapy.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB13406

  • Survivin, MMP-2, MT1-MMP, and TIMP-2: their impact on survival, implantation, and proliferation of endometriotic tissues. 23011643

    In order to study survivin, matrix metalloproteinases (MMP-2), membranous type 1 matrix metalloproteinase (MT1-MMP), and tissue inhibitor metalloproteinase-2 (TIMP-2) expression immunohistochemically in endometriotic tissues and normal endometrium, our retrospective study considered 194 patients affected by endometriosis and 71 patients with normal endometrium. Tissue microarrays were created from paraffin-embedded blocks; immunohistochemistry was used to assess protein expression. In endometriotic tissues, survivin was expressed at a higher level than in normal endometrium; its glandular expression level was higher in non-ovarian than in ovarian endometriotic tissues and lower in stromal components. Endometrial tissues from women without endometriosis and endometriotic tissues had different matrix metalloproteinase expression profiles. MMP-2 and MT1-MMP correlated with TIMP-2 in endometriotic tissues. Furthermore, in endometriotic tissues, expression of survivin, aurora B kinase, and Ki-67 showed a significant positive correlation, which indicates a role in cellular proliferation that could be closely linked to its anti-apoptotic activity in endometriosis development. Our results imply a role for matrix metalloproteinases in endometriosis invasiveness; correlation of their expression with that of TIMP-2 underscores its possible key regulatory role.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    AB6004
    Produktbezeichnung:
    Anti-MT1-MMP Antibody, hinge region

  • Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. 7927938

    The 72-kDa (MMP-2, gelatinase A) and the 92-kDa (MMP-9, gelatinase B) matrix metalloproteinases have been associated with tumor cell invasion and metastasis. Immunohistological staining of MMP-2 and MMP-9, basal lamina collagen IV and TIMP-2 were performed on frozen sections of 83 invasive breast carcinomas. MMP-2 and MMP-9 were associated with neoplastic cell plasma membrane in 72% of cases and exhibited inter-tumoral variability of staining intensity. MMP-2 and MMP-9 staining was not correlated with presence of metastases at time of diagnosis or with disease outcome. TIMP-2 was detected in the peri-tumoral stroma and was present in 87% of cases. Residual benign breast tissue was negative for TIMP-2 staining. Neoplasms with diffuse TIMP-2 staining (24%) recurred significantly more frequently (75% recurred) than cases with focal (42% recurred) or absent (27% recurred) TIMP-2. Presence of collagen IV was negatively correlated with gelatinase staining. We conclude that up-regulation of MMP-2 and MMP-9 expression in breast tumor cells is reciprocally correlated to collagen IV staining. Clinical outcome, however, is more closely related to the presence of TIMP-2 than the corresponding MMPs. Enhanced TIMP-2 expression, therefore, may denote a stromal response to tumor invasion, indicative of aggressive behavior in a subset of breast carcinomas.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB13415
    Produktbezeichnung:
    Anti-MMP-9 Antibody, clone GE-213

  • Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice. 21285317

    Circulating levels of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are altered in human obesity and may contribute to its pathology. TIMP-2 exerts MMP-dependent (MMP inhibition and pro-MMP-2 activation) and MMP-independent functions. To assess the role of TIMP-2 in a murine model of nutritionally induced obesity, weight gain in wild-type and TIMP-2 deficient [knockout (KO)] mice fed a chow or high-fat diet (HFD) was determined. The effects of diet on glucose tolerance and insulin sensitivity, as well as pancreatic β-cell and adipocyte physiology, were assessed. Chow-fed TIMP-2 KO mice of both sexes became obese but maintained relatively normal glucose tolerance and insulin sensitivity. Obesity was exacerbated on the HFD. However, HFD-fed male, but not female, TIMP-2 KO mice developed insulin resistance with reduced glucose transporter 2 and pancreatic and duodenal homeobox 1 levels, despite increased β-cell mass and hyperplasia. Thus, although β-cell mass was increased, HFD-fed male TIMP-2 KO mice develop diabetes likely due to β-cell exhaustion and failure. TIMP-2 mRNA, whose expression was greatest in sc adipose tissue, was down-regulated in HFD-fed wild-type males, but not females. Furthermore, HFD increased membrane type 1-MMP (MMP-14) expression and activity in male, but not female, sc adipose tissue. Strikingly, MMP-14 expression increased to a greater extent in TIMP-2 KO males and was associated with decreased adipocyte collagen. Taken together, these findings demonstrate a role for TIMP-2 in maintaining extracellular matrix integrity necessary for normal β-cell and adipocyte physiology and that loss of extracellular matrix integrity may underlie diabetic and obesogenic phenotypes.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    07-1402

  • Inhibited angiogenesis in aging: a role for TIMP-2. 14528035

    Factors responsible for age-associated impairment of angiogenesis are poorly understood. We observed that in aged mice, new fibrovascular tissue within subcutaneous polyvinyl alcohol sponges expressed more tissue inhibitor of metalloproteinases (TIMP)-2 than did corresponding tissue from young mice. In complementary studies in vitro, we utilized young and aged human microvascular endothelial cell lines (hmEC36 and hmEC90, respectively) and compared their morphogenetic capacity within three-dimensional collagen. HmEC90 exhibited poor formation of tubular, capillary-like structures in vitro, diminished expression of active matrix metalloproteinase (MMP)-2, and similar or lesser amounts of MT1-MMP relative to hmEC36. Correspondingly, the MMP inhibitor GM6001 decreased tubulogenesis by hmEC36 to levels observed for hmEC90. In vitro, hmEC90 expressed similar quantities of TIMP-1, but more TIMP-2 than did hmEC36. Accordingly, purified TIMP-2 inhibited tubulogenesis by hmEC36. Collectively, our studies indicate that elevated levels of TIMP-2 modulate decreased angiogenesis in aged tissues, most likely via TIMP-2-mediated inhibition of MMP-2 and MT1-MMP.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB3310
    Produktbezeichnung:
    Anti-TIMP-2 Antibody, clone 67-4H11

  • Domain structure of human 72-kDa gelatinase/type IV collagenase. Characterization of proteolytic activity and identification of the tissue inhibitor of metalloproteinase- ... 1322396

    The 72-kDa gelatinase/type IV collagenase, a metalloproteinase thought to play a role in metastasis and in angiogenesis, forms a noncovalent stoichiometric complex with the tissue inhibitor of metalloproteinase-2 (TIMP-2), a potent inhibitor of enzyme activity. To define the regions of the 72-kDa gelatinase responsible for TIMP-2 binding, a series of NH2- and COOH-terminal deletions of the enzyme were constructed using the polymerase chain reaction technique. The full-length and the truncated enzymes were expressed in a recombinant vaccinia virus mammalian cell expression system (Vac/T7). Two truncated enzymes ending at residues 425 (delta 426-631) and 454 (delta 455-631) were purified. Like the full-length recombinant 72-kDa gelatinase, both COOH-terminally truncated enzymes were activated with organomercurial and digested gelatin and native collagen type IV. In contrast to the full-length enzyme, delta 426-631 and delta 455-631 enzymes were less sensitive to TIMP-2 inhibition requiring 10 mol of TIMP-2/mol of enzyme to achieve maximal inhibition of enzymatic activity. The activated but not the latent forms of the delta 426-631 and delta 455-631 proteins formed a complex with TIMP-2 only when excess molar concentrations of inhibitor were used. We also expressed the 205-amino acid COOH-terminal fragment, delta 1-426, and found that it binds TIMP-2. In addition, a truncated version of the 72-kDa gelatinase lacking the NH2-terminal 78 amino acids (delta 1-78) of the proenzyme retained the ability to bind TIMP-2. These studies demonstrate that 72-kDa gelatinases lacking the COOH-terminal domain retain full enzymatic activity but acquire a reduced sensitivity to TIMP-2 inhibition. These data suggest that both the active site and the COOH-terminal tail of the 72-kDa gelatinase independently and cooperatively participate in TIMP-2 binding.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB13405

  • The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by ... 8663332

    It has been proposed that the cell-mediated activation of progelatinase A requires binding of the C-terminal domain of the proenzyme to a membrane-associated complex of the membrane type matrix metalloproteinase MT1-MMP and TIMP-2. Subsequent sequential proteolysis of the propeptide by MT1-MMP and gelatinase A is thought to generate the active form of gelatinase A. We have prepared the proform of the catalytic domain of the MT1-MMP and demonstrated that this may be activated in vitro by trypsin proteolysis to yield a functional proteinase capable of cleaving typical metalloproteinase peptide substrates, gelatin and casein. The active catalytic domain of MT1-MMP was also shown to activate progelatinase A to a fully active form. Using the inactive mutant pro-E375A gelatinase A, we dissected the propeptide processing events that occur. MT1-MMP cleaves the propeptide at the sequence Asn37-Leu38 only. Further cleavage of the mutant enzyme propeptide at Asn80-Tyr81, equivalent to that of the active wild type gelatinase A, could only be effected by addition of gelatinase A to the system. TIMP-1 was essentially unable to prevent MT1-MMP processing of wild type or E375A progelatinase A, whereas TIMP-2 and TIMP-3 were good inhibitors of these events. Analysis of the rate of binding of TIMPs to the catalytic domain of MT1-MMP using kinetic methods showed that TIMP-1 is an extremely poor inhibitor of MT1-MMP. In comparison, TIMP-2 and TIMP-3 are excellent inhibitors, binding more rapidly to the catalytic domain of MT1-MMP than to the catalytic domain of gelatinase A. These data demonstrate the basic mechanism of MT1-MMP action on progelatinase A and the reason for the lack of inhibition by TIMP-1 previously demonstrated in cell-based activation studies.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    CC1043
    Produktbezeichnung:
    MMP-14, human, prodomain, catalytic domain, and hemopexin domain, E. coli recombinant

  • Ascorbate-induced osteoblast differentiation recruits distinct MMP-inhibitors: RECK and TIMP-2. 18989628

    The bone formation executed by osteoblasts represents an interesting research field both for basic and applied investigations. The goal of this work was to evaluate the molecular mechanisms involved during osteoblast differentiation in vitro. Accordingly, we demonstrated that, during the osteoblastic differentiation, TIMP-2 and RECK presented differential expressions, where RECK expression was downregulated from the 14th day in contrast with an increase in TIMP-2. Concomitantly, our results showed a temporal regulation of two major signaling cascades during osteoblast differentiation: proliferation cascades in which RECK, PI3 K, and GSK-3beta play a pivotal role and latter, differentiation cascades with participation of Ras, Rho, Rac-1, PKC alpha/beta, and TIMP-2. Furthermore, we observed that phosphorylation level of paxillin was downregulated while FAK(125) remained unchangeable, but active during extracellular matrix (ECM) remodeling. Concluding, our results provide evidences that RECK and TIMP-2 are involved in the control of ECM remodeling in distinct phases of osteoblast differentiation by modulating MMP activities and a multitude of signaling proteins governs these events.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    05-778
    Produktbezeichnung:
    Anti-Rho (-A Antibody, -B, -C), clone 55

  • Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2. 24704830

    Emerging evidence has shown that cancer stem cells (CSCs) are the cellular determinants to promote cancer invasion and metastasis. However, the mechanism underlying CSC invasion remains unknown. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression, and their expressions are often dysregulated in cancers. In the present study, we demonstrated that two functionally related microRNAs, miR-20a and -106a (miR-20a/106a), were capable of enhancing the invasiveness of CD133(+) glioma stem cells (GSCs) isolated from both glioblastoma cell line U87 and primary human glioma specimens. We found that the level of miR-20a/106a in GSCs was significantly higher than that in the committed CD133(-) glioma cells, and correlated with the invasive capability of GSCs. By bioinformatic analysis, we identified tissue inhibitor of metalloproteinases-2 (TIMP-2) as one of the miR-20a/106a-targeted genes. TIMP-2 level correlated inversely with miR-20/106 expression. Directly targeting by miR-20a/106a on 3'-untranslation region (3'-UTR) of TIMP-2 mRNA was confirmed by 3'-UTR dual-luciferase reporter assay. Knockdown of miR-20a/106a in GSCs increased endogenous TIMP-2 protein abundance, thereby inhibiting GSC invasion. We also found that Nordy, a synthetic lipoxygenase inhibitor, inhibited GSC invasiveness by elevating the expression of TIMP-2 via downregulation of miR-20a/106a. Our results indicate that miR-20a/106a has a key role in GSC invasion and may serve as targets for treatment of glioblastoma.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    17-371
    Produktbezeichnung:
    EZ-ChIP™