Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenotypic changes of integrin and metalloproteinase secretion of the invasive human cytotrophoblast are regulated by cytokines and growth factors, but how this occurs is not completely understood. We used 24-h cytotrophoblast cultures from first trimester pregnancies to investigate the effects of leptin and cytokines on the expression of the alpha2, alpha5, and alpha6 integrin subunits and on the activity of metalloproteinase-2 (gelatinase A) and metalloproteinase-9 (gelatinase B). The alpha2 subunit was marginally upregulated by leptin and interleukin-1alpha (IL-1alpha). All compounds tested upregulated, in some degree, the alpha5 expression. The a6 integrin subunit was massively upregulated, by leptin, interleukins, and transforming growth factor-beta. None of the factors tested affected metalloproteinase-2 activity, but the activity of metalloproteinase-9 was upregulated by leptin and IL-1alpha. In conclusion, leptin and IL-1alpha actively induce some of the changes that cytotrophoblasts undergo to achieve a more invasive phenotype. A novel role for leptin is proposed during early pregnancy: leptin might be an autocrine/paracrine regulator of cytotrophoblast invasiveness during implantation and placentation.
 ...
PMID:Effects of leptin, interleukin-1alpha, interleukin-6, and transforming growth factor-beta on markers of trophoblast invasive phenotype: integrins and metalloproteinases. 1172 Feb 41

We reconstituted a three-dimensional gastric carcinoma model similar to invasive gastric carcinoma tissue. This model consists of a human gastric carcinoma cell line, GCTM-1, a human fibroblast cell line, TIG-1-20, and transforming growth factor-beta (TGF-beta)-containing type I collagen gel. Using this model, we were able to observe the growth of the two cell types, especially carcinoma cell invasive growth, in real time for more than 30 days. TGF-beta and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-beta induced the enhanced expression of matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) in GCTM-1 at both the protein and enzymatic activity levels. The TGF-beta-induced invasion of GCTM-1 was inhibited by MMP9- or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-gamma (IFN-gamma) was added to this model, TGF-beta-dependent GCTM-1 invasion was significantly inhibited, concomitant with the decreased expression of MMP9 and uPA. The intracellular signal transduction of Smad was examined to analyse the mechanism of the inhibitory effect of IFN-gamma. TGF-beta accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3-Smad4 complex in GCTM-1, but these TGF-beta-induced effects were significantly inhibited by IFN-gamma-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGF-beta-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-gamma on TGF-beta-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-gamma inhibits TGF-beta-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-gamma may be a new therapeutic tool for TGF-beta-expressed invasive carcinomas.
 ...
PMID:Interferon-gamma suppresses transforming growth factor-beta-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. 1458 10

We have shown recently that the hyaluronan receptor, CD44, and matrix metalloproteinase 9 (MMP-9) form a complex on the surface of TA/St mouse mammary carcinoma cells that activates latent transforming growth factor-beta (TGF-beta) and is required for tumor invasion. Disruption of the CD44/MMP-9 complex by expression of soluble CD44 results in the loss of tumor invasiveness and abrogates tumor cell survival in host lung parenchyma following intravenous injection into syngeneic mice. To explore the molecular nature of the survival signals derived from the CD44/MMP-9 complex during the development of tumor metastasis, we investigated the possibility that activation of latent TGF-beta by the CD44/MMP-9 complex is responsible for tumor cell survival in host lung parenchyma. TA3 cells overexpressing dominant negative soluble CD44 (TA3sCD44), which compromises native CD44 function and the ability of TA3 cells to develop metastases, were transfected with constitutively active or latent TGF-beta2 and tested for their ability to form tumors in syngeneic mice. Our results demonstrate that expression of the constitutively active, but not the latent, form of TGF-beta2 rescues TA3sCD44 cells from apoptosis during lung colonization. These observations provide evidence that activation of latent TGF-beta constitutes an event downstream of CD44-dependent signals that is required for tumor cell survival and metastatic colony formation. The functional axis composed of CD44, MMP-9 and TGF-beta may therefore play an important role in the metastatic proclivity of selected tumor types.
 ...
PMID:Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. 1538 73

Congenital obstructive nephropathy is the primary cause for end-stage renal disease (ESRD) in children. An increasingly used animal model of obstructive nephropathy is unilateral ureteral obstruction (UUO). This model mimics, in an accelerated manner, the different stages of obstructive nephropathy leading to tubulointerstitial fibrosis: cellular infiltration, tubular proliferation and apoptosis, epithelial-mesenchymal transition (EMT), (myo)fibroblast accumulation, increased extracellular matrix (ECM) deposition, and tubular atrophy. During the last decade genetically modified animals are increasingly used to study the development of obstructive nephropathy. Although the use of these animals (mainly knockouts) has highlighted some pitfalls of this approach (compensation by closely related gene products, absence of temporal knockouts) it has brought important information about the role of specific gene-products in the pathogenesis of obstructive nephropathy. Besides confirming the important pathologic role for angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) in obstructive nephropathy, these animals have shown the complexity of the development of tubulointerstitial fibrosis involving a large number of closely functionally related molecules. More interestingly, the use of these animals has led to the discovery of unexpected and contradictory roles (both potentially pro- and antifibrotic) for Ang II, for ECM degrading enzymes matrix metalloproteinase 9 (MMP-9) and tissue plasminogen activators (PAs), for plasminogen activator inhibitor 1 (PAI-1), and for the adhesion molecule osteopontin (OPN) in obstructive nephropathy. Further use of these animals, especially in combination with pharmacologic tools, should help to better identify potential antifibrotic strategies in obstructive nephropathy.
 ...
PMID:Obstructive nephropathy: insights from genetically engineered animals. 1610 23

Increased transforming growth factor-beta (TGF-beta) signaling has been observed at the tumor-bone interface of mammary tumor-induced osteolytic lesions despite no observed transcriptional up-regulation of TGF-beta. To this point, the mechanism for enhanced TGF-beta signaling remains unclear. The bulk of TGF-beta that is released at the tumor-bone interface is in an inactive form secondary to association with beta-latency-associated protein and latency TGF-beta binding protein. We hypothesized that the observed increase in TGF-beta signaling is due to increased cathepsin G-dependent, matrix metalloproteinase 9 (MMP9)-mediated activation of latent TGF-beta. MMP9 is capable of activating latent TGF-beta, and we observed that decreased production of MMP9 was associated with reduced TGF-beta signaling. Similar to TGF-beta, MMP9 is released in an inactive form and requires proteolytic activation. We showed that cathepsin G, which we have previously shown to be up-regulated at the tumor-bone interface, is capable of activating pro-MMP9. Inhibition of cathepsin G in vivo significantly reduced MMP9 activity, increased the ratio of latent TGF-beta to active TGF-beta, and reduced the level of TGF-beta signaling. Our proposed model based on these results is that cathepsin G is up-regulated through tumor-stromal interactions and activates pro-MMP9, active MMP9 cleaves and releases active TGF-beta, and active TGF-beta can then promote tumor growth and enhance osteoclast activation and subsequent bone resorption. Thus, for the first time, we have identified cathepsin G and MMP9 as proteases involved in enhanced TGF-beta signaling at the tumor-bone interface of mammary tumor-induced osteolytic lesions and have identified these proteases as potential therapeutic targets.
 ...
PMID:Cathepsin G-mediated activation of pro-matrix metalloproteinase 9 at the tumor-bone interface promotes transforming growth factor-beta signaling and bone destruction. 1967 89

We investigated the effects of epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) on cell growth and on regulation of matrix metalloproteinases (MMPs) in four cell lines of human esophageal squamous cell carcinomas (TE8, TE9, TE10, and TE11). EGF stimulated the production of proforms of gelatinase B (MMP-9) by three cell lines that could synthesize EGF by themselves, with TE9 being the exception. Particularly, both the production of MMP-9 and DNA synthesis in TE10 were stimulated significantly by EGF. TGF-beta slightly stimulated DNA synthesis in two cell lines, TE9 and TE11, and TGF-beta secretion by TE9 was detected. The production of proforms of gelatinases A (MMP-2) and MMP-9 was gradually induced by TGF-beta in a concentration-dependent manner in all the cell lines except for TE9. Flow cytometric analysis revealed that all the lines expressed both EGF- and TGF-beta-receptors. In conclusion, our present results indicate that at least there are possibly two distinct phenotypes in human esophageal squamous cell carcinoma: one (TE10) depends on autocrine EGF production that enhances DNA synthesis and MMP-9 production; and the other (TE9) on autocrine TGF-beta that stimulates DNA synthesis but not in relation to gelatinase production.
 ...
PMID:Phenotypes of human esophageal squamous cell carcinoma based on matrix metalloproteinase production. 2153 72


<< Previous 1 2