Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavobacterium meningosepticum, Elder strain (ATCC 33958), secretes into the medium a neutral zinc endoprotease as a major component of the extracellular proteins. The enzyme was purified to homogeneity in a simple two-step procedure involving ammonium sulfate precipitation and hydrophobic interaction chromatography. The molecular weight of this metalloprotease was determined to be about 27,000 (P27) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. P27 was comparable to thermolysin in the relative rates of elastin-orcein, azocasein, and azoalbumin hydrolysis. P27 and thermolysin hydrolyzed equally well 2,4-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg and 2,4-dinitrophenyl-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2 at the same primary sites that are susceptible to cleavage by vertebrate collagenases, Gly-Ile, and Gly-Leu. P27 was also capable of partially hydrolyzing Type I acid-soluble calf skin collagen and slowly hydrolyzing N-[3-(2-furyl)acryloyl]-Leu-Gly-Pro-Ala, a bacterial collagenase substrate not cleaved by thermolysin. P27 was further differentiated from thermolysin from the inability of the former to hydrolyze N-[3-(2-furyl)acryloyl]-Gly-Leu-NH2. In addition, a vertebrate elastase substrate succinyl-Ala-Ala-Ala-p-nitroanilide was hydrolyzed by P27 but not by thermolysin. P27 is a newly described and unique enzyme from the standpoint of substrate specificity and from the fact that it is resistant to inhibition by phosphoramidon, an inhibitor of a number of zinc endopeptidases, including thermolysin.
 ...
PMID:Purification and characterization of a neutral zinc endopeptidase secreted by Flavobacterium meningosepticum. 818 8

P27, an inhibitor of cyclin-dependent kinases, plays an important role in the control of cell adhesion and contact inhibition-dependent cell cycle regulation. Hepatocytes, maintained in primary culture, offer a model of synchronized primary epithelial cells which retain a differentiated profile while stimulated to proliferate. We therefore investigated the pattern of endogenous p27 expression in cyclin rat hepatocytes isolated by collagenase perfusion followed by mitogenic stimulation. P27 was expressed in whole normal liver and freshly isolated hepatocytes. We then observed a sharp decrease in p27 levels, concomitant with the progression in early-mid G1, followed by reaccumulation in late G1 and the G1/S transition. Immunochemistry and BrdU labelling demonstrated nuclear localization of p27 and its expression in cells engaged in both G1 and S phase. P27 was detected in late G1 in complexes containing cyclins D1, E and A. Cyclin E- and A-associated kinase activities, however, were detected at the G1/S transition and depletion experiments confirmed that most active complexes were free of p27. Phosphorylated forms of p27 were detected in unstimulated and stimulated hepatocytes in both early-mid G1 and G1/S. Finally, two-dimensional gel electrophoresis showed evidence for several forms of p27 with a distinct profile of distribution in quiescent and stimulated hepatocytes. Collectively, our data offer a model in which p27 shows a biphasic profile of accumulation, with the early decrease possibly involved in the progression through early and mid G1. In contrast with most cell types tested so far, the late G1 accumulation did not impair formation of active cyclin E- and A associated kinases, and thus G1/S transition.
 ...
PMID:Differential expression of the cyclin-dependent kinase inhibitor P27 in primary hepatocytes in early-mid G1 and G1/S transitions. 1046 2

Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by alpha-tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
 ...
PMID:Regulation of gene expression by alpha-tocopherol. 1531 6

S-phase kinase-associated protein-2 (Skp2) is overexpressed in human cancers and acted as an oncogenic protein associated with poor prognosis by enhancing tumor metastasis. The present study has demonstrated that Skp2 overexpresses stable transfectants from 786-0 human renal cancer cells. We found that these stable transfectants exhibited increased migratory and invasive abilities. In addition, expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was upregulated and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was downregulated. In contrast, RNA interference-mediated knockdown Skp2 expression suppressed the ability of ACHN cells to migratory and invasive. Skp2 depletion increased P27 and decreased cyclin E activity, and then induced cell cycle arrest in the G0/G1 phase. Skp2 depletion also downregulated MMP-2 and MMP-9, while upregulated the TIMP-1 activity and expression. The results suggest that Skp2 signaling pathways promoted the ability to metastasize, by stimulating cell proliferation and increasing the ratio of MMP-2 and MMP-9/TIMP-1. So, in conclusion, we provide the first evidence that the imbalance of MMP/TIMP, including upregulation of MMP-2 and MMP-9 and downregulation of TIMP-1, is one of the mechanisms by which Skp2 promotes cell invasion.
 ...
PMID:Imbalance between MMP-2, 9 and TIMP-1 promote the invasion and metastasis of renal cell carcinoma via SKP2 signaling pathways. 2498 70

Cardiac fibroblasts (CFs) play a key role in cardiac fibrosis by regulating the balance between extracellular matrix synthesis and breakdown. Although phosphatase and tensin homologue on chromosome 10 (PTEN) has been found to play an important role in cardiovascular disease, it is not clear whether PTEN is involved in functional regulation of CFs. In the present study, PTEN was overexpressed in neonatal rat CFs via recombinant adenovirus-mediated gene transfer. The effects of PTEN overexpression on cell-cycle progression and angiotensin II- (Ang II-) mediated regulation of collagen metabolism, synthesis of matrix metalloproteinases, and Akt/P27 signaling were investigated. Compared with uninfected cells and cells infected with green fluorescent protein-expressing adenovirus (Ad-GFP), cells infected with PTEN-expressing adenovirus (Ad-PTEN) significantly increased PTEN protein and mRNA levels in CFs (P < 0.05). The proportion of CFs in the G1/S cell-cycle phase was significantly higher for PTEN-overexpressing cells. In addition, Ad-PTEN decreased mRNA expression and the protein synthesis rate of collagen types I and III and antagonized Ang II-induced collagen synthesis. Overexpression of PTEN also decreased Ang II-induced matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1) production as well as gelatinase activity. Moreover, Ad-PTEN decreased Akt expression and increased P27 expression independent of Ang II stimulation. These results suggest that PTEN could regulate its functional effects in neonatal rat CFs partially via the Akt/P27 signaling pathway.
 ...
PMID:Effect of Phosphatase and Tensin Homologue on Chromosome 10 on Angiotensin II-Mediated Proliferation, Collagen Synthesis, and Akt/P27 Signaling in Neonatal Rat Cardiac Fibroblasts. 2774 25