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51.
Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13 总被引:29,自引:0,他引:29
Nyberg P Heikkilä P Sorsa T Luostarinen J Heljasvaara R Stenman UH Pihlajaniemi T Salo T 《The Journal of biological chemistry》2003,278(25):22404-22411
Endostatin, a 20-kDa collagen XVIII fragment, inhibits angiogenesis and tumor growth in vivo, but the mechanisms are still unclear. Matrix metalloproteases (MMPs), a family of extracellular and membrane-associated endopeptidases, collectively digest almost all extracellular matrix and basement membrane components, and thus play an important role in tumor progression. We studied the effects of recombinant human endostatin on human MMP-2, -9, -8, and -13. We found that endostatin inhibited the activation and catalytic activity of pro-MMP-9 and -13 as well as recombinant pro-MMP-2. It prevented the fragmentation of pro-MMP-2 that was associated with reduction of catalytic activity. Endostatin had no effect on MMP-8 as shown by collagenase activity assays. An in vitro migration assay and an in vivo chicken chorioallantoic membrane intravasation assay with the human tongue squamous cell carcinoma cell line HSC-3 revealed the biphasic nature of endostatin; low endostatin concentrations inhibited intravasation and migration of these cells in a dose-dependent manner, but at increased concentrations, the inhibitory effect was far less efficient. The results show that endostatin blocks the activation and activities of certain tumor-associated pro-MMPs, such as pro-MMP-2, -9, and -13, which may explain, at least in part, the antitumor effect of endostatin. Our results also suggest that endostatin inhibits tumor progression by directly affecting the tumor cells and not just acting via endothelial cells and blockage of angiogenesis. 相似文献
52.
De Witt BJ Kaye AD Ibrahim IN Bivalacqua TJ D'Souza FM Banister RE Arif AS Nossaman BD 《American journal of physiology. Lung cellular and molecular physiology》2001,280(1):L50-L57
The effects of G?-6976, a Ca(2+)-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-delta isozyme/calmodulin (CaM)-dependent kinase III inhibitor, on responses to vasopressor agents were investigated in the feline pulmonary vascular bed. Injections of angiotensin II, norepinephrine (NE), serotonin, BAY K 8644, and U-46619 into the lobar arterial constant blood flow perfusion circuit caused increases in pressure. G?-6976 reduced responses to angiotensin II; however, it did not alter responses to serotonin, NE, or U-46619, whereas G?-6976 enhanced BAY K 8644 responses. Rottlerin reduced responses to angiotensin II and NE, did not alter responses to serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochemistry of feline pulmonary arterial smooth muscle cells demonstrated localization of PKC-alpha and -delta isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-alpha and -delta isozymes decreased with administration of G?-6976 and rottlerin, respectively. These data suggest that activation of Ca(2+)-dependent PKC isozymes and Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate responses to NE. A rottlerin- or G?-6976-sensitive mechanism is not involved in mediating responses to serotonin and U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 responses in the feline pulmonary vascular bed. 相似文献
53.
In this study, the effect of pH on the conformation and the reactivity of the Escherichia coli Hsp70 molecular chaperone DnaK was investigated using spectroscopic and chemical assays. DnaK exhibits negligible binding of the hydrophobic dye 1-anilino-naphthalene-8-sulfonate (ANS) between pH 7 to 5.0, whereas appreciable binding occurs between pH 4.5 to 4.0. The binding of ANS to a protein is diagnostic of the presence of accessible ordered hydrophobic surfaces. Such hydrophobic surfaces are often displayed by partially folded protein intermediates such as molten globules. Nucleotide inhibits 70% of the ANS binding at pH 4.5 but none of the ANS binding at pH 4.0. Proteolysis of nucleotide-free DnaK at pH 4.5 with cathepsin D yields detectable fragments (masses > 20 kDa) of the C-terminal peptide-binding domain but none of the N-terminal ATPase domain, thus the ATPase domain is preferentially targeted for proteolysis. In contrast, proteolysis of nucleotide-free DnaK at pH 4.0 with cathepsin D cuts near the linker region, yielding both functional domains. Our interpretation of these data is that incubation of DnaK at pH 4.5 produces a partially unfolded form of the ATPase domain, in which secondary structure is mainly intact, but tertiary structure is reduced. Incubation of the protein at pH 4.0 produces an intermediate in which both functional domains have collapsed and possibly separated. Nucleotide inhibits the conformational change that occurs at pH 4.5 but not at 4.0. 相似文献
54.
Kristen U Bischoff N Lisboa S Schirmer E Witt S Quader H 《Alternatives to laboratory animals : ATLA》2002,30(3):323-329
Tobacco pollen tubes were used as a standard in vitro system to investigate cell growth aberrations caused by some of the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme chemicals and other toxic compounds. Changes in cytoskeletal pattern were observed in the tube cells by using tubulin immunofluorescence and rhodamin-phalloidin fluorescence for the localisation of microtubules and actin filaments, respectively. Four different types of cell malformation were found: screw-like growth, isodiametric tip swelling, hook formation, and pollen grain enlargement. We suggest that these malformations resulted from an interference by the chemicals with the cytosolic calcium gradient which controls tip growth and the orientation of the pollen tube. The results may contribute to a general understanding of toxicity-based cell malformations. 相似文献
55.
56.
We discuss recent experiments that have illuminated individual steps in the reaction cycle of the Escherichia coli Hsp70 molecular chaperone DnaK. Using this new information, we compare two distinctly different global mechanisms of action--holding versus unfolding--and argue that the available evidence suggests that DnaK is an unfoldase. 相似文献
57.
Johnson KP Weckstein JD Witt CC Faucett RC Moyle RG 《Molecular phylogenetics and evolution》2002,23(2):150-157
The taxonomy of lice (Insecta: Phthiraptera) is often heavily influenced by host taxonomy. The use of host information to define genera of avian lice in the widespread Degeeriella complex has been prevalent but has created problems. Several workers have suggested that genera defined on the basis of host association are not monophyletic. We used sequences of nuclear (elongation factor-1alpha) and mitochondrial (cytochrome oxidase I) genes to test the monophyly of several genera in the Degeeriella complex. Parsimony and likelihood analyses of these data indicated that many genera in the Degeeriella complex are not monophyletic, such that species occurring on the same host groups do not form monophyletic groups. Biological features of hosts (including predaceous habits, brood parasitism, and hole nesting) for species in the Degeeriella complex likely provide opportunities for switching of lice between host groups. In addition, dispersal of lice via phoresy on hippoboscid flies also likely provides opportunities for host switching in the Degeeriella complex. This study indicates that the overuse of host taxonomy in louse taxonomy can result in classifications that do not reflect phylogenetic history. 相似文献
58.
In territorial microtines intra-specific density dependent processes can limit the maturation of individuals during the summer of their birth. This may have demographic consequences by affecting the number and the age distribution of breeding individuals in the population. Little is known about this process on a community level, though populations of many northern microtine species fluctuate in synchrony and are known to interfere socially with each other. We experimentally studied the influence of the field vole Microtus agrestis on maturation, breeding, space use and survival of weanling bank voles, Clethrionomys glareolus. Two additive competition experiments on bank vole populations were conducted in large outdoor enclosures, half of them additionally housing a field vole population. In a mid-summer experiment low population density and absence of older breeding females minimised intra-specific competition. Survival was not affected by the presence of field voles. Season had a significant effect on both the probability of maturation and breeding of the weanlings. Competition with field voles significantly delayed breeding, and coupled with seasonal effects decreased the probability of breeding. In a late-summer experiment breeding and survival of bank vole weanlings were studied for three weeks as part of a high density breeding bank vole population. Weanlings did not mature at all nor were their space use and survival affected by the presence of field voles. Our results show that competition with other species can also have an impact on breeding of immatures. In an extreme seasonal environment, even a short delay of breeding may decrease survival chances of offspring. Seasonal and competition effects together may thus limit the contribution of year born females to reproductive output of the population. Other studies have shown that adult breeding bank voles suffer lower survival in the presence of field voles, but this study showed no survival effects on the weanlings. Thus it might be beneficial for weanlings to stay immature especially in the end of the breeding season and postpone reproduction to the next breeding season if densities of competing species are high. 相似文献
59.
DnaK, the Escherichia coli Hsp70, possesses two functional domains, the N- and C-terminal ATPase and peptide-binding domains, respectively. Elucidation of the mechanism of allosteric coupling between the two domains is key to understanding how Hsp70 chaperones interact with their substrates. We previously reported that ATP reacts with wild-type DnaK-peptide complexes according to the two-step reaction, ATP + DnaK-P if ATP-DnaK-P if ATP-DnaK + P, where ATP binds in the first step, and a conformational change that quenches DnaK's tryptophan fluorescence (denoted by the asterisk) and expels bound peptide occurs in the second step. Here we report that DnaK(2-517), a lidless variant, also reacts with ATP and peptide by this two-step mechanism. Compared to wild-type DnaK, we found that, depending on the sequence of the bound peptide and the temperature, deletion of the lid produces a 27- to 66-fold increase in the rate constant (k(2)) for the ATP-triggered conformational change (ATP-DnaK-P --> ATP-DnaK+P) but only a approximately 2-fold increase in the rate constant (k(-)(2)) for the reverse reaction (ATP-DnaK+P --> ATP-DnaK-P). A model is proposed in which the lid regulates the rate of interdomain communication by retarding motions within the beta-sandwich that occur as a consequence of ATP binding. New evidence in support of the reversible, two-step conformational switch mechanism is also presented. 相似文献
60.
Infection of cells with replication deficient adenovirus induces cell cycle alterations and leads to downregulation of E2F-1 总被引:1,自引:0,他引:1
Kuhn H Liebers U Gessner C Karawajew L Ruppert V Schumacher A Witt C Wolff G 《Biochimica et biophysica acta》2002,1542(1-3):106-115
Gene products of recombinant replication-deficient adenovirus vectors of the first generation (Ad vector) can induce cell cycle dysregulation and apoptosis after infection in eukaryotic cells. The mechanisms underlying this complex process are largely unknown. Therefore, we investigated the regulation of the pRb/E2F-1 complex, which controls transition from G(0)/G(1) to S phase of the cell cycle. As Ad vector infection results in a decrease in the number of cells in G(0)/G(1) phase of the cell cycle, we observed a decline of the pRb protein level and, surprisingly, also a decrease of the E2F-1 protein and mRNA level in infected cell lines. Furthermore, in contrast to the reduction of cells in the G(0)/G(1) phase we observed increased protein levels of p53 and p21 proteins. However, as experiments in p53 deficient cell lines indicated, the decrease of pRb and E2F-1 is independent of p53 and p21 expression. Moreover, results obtained with Rb deficient cell lines indicated that the reduced E2F-1 expression is independent of pRb. These results suggest that Ad vector-induced cell cycle dysregulation is associated with a specific downregulation of E2F-1 independent of Rb and p53 genomic status of cells. 相似文献