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1.
Increased transglutaminase activity was associated with IL-6 release in cultured human gingival fibroblasts exposed to dental cast alloys 总被引:1,自引:0,他引:1
Summary. Molecular mechanisms underlying gingival and periodontal inflammation caused by dental alloys are still poorly understood.
Recently, it has been demonstrated that tissue transglutaminase can be involved in inflammatory cell response. The aim of
this study was to evaluate effects of exposure to orthodontic materials on transglutaminase in cultured human gingival fibroblasts.
The incubation with Ni–Ti heat-activated (T3) or Ni–Ti super-elastic (T4), and with Ni–Cr–Co (T2) alloys produced respectively
2.5-fold and 8-fold increases in IL-6 release compared with control cultures. Transglutaminase activity was significantly
increased in cells exposed to T3 and T4 alloys (about 170% of control; p < 0.05), where it was mainly localized close to inner part of cell membrane. The exposure to T3 and T4 specimens significantly
up-regulated also tTG expression compared with control cultures. These data first show an association between IL-6 release
and tissue transglutaminase increases, suggesting that TGase-mediated reactions may play a major role in periodontal inflammation. 相似文献
2.
Summary. Basic biological processes in which tissue transglutaminase (TG2, tTG) is thought to be important including apoptosis, cell
adhesion and migration, ECM homeostasis and angiogenesis are key stages in the multistage tumour progression cascade. Studies
undertaken with primary tumours and experimental models suggest that TG2 expression and activity in the tumour body and surrounding
matrix generally decreases with tumour progression, favouring matrix destabilisation, but supporting angiogenesis and tumour
invasion. In contrast, in the secondary metastatic tumour TG2 is often highly expressed whereby its potential roles in cell
survival both at the intra- and extracellular level become important. In the following review the underlying molecular basis
for the selection of these different phenotypes in tumour types and the anomaly for the requirement of TG2 is discussed in
relation to the complex events of tumour progression. 相似文献
3.
Lentini A Provenzano B Caraglia M Shevchenko A Abbruzzese A Beninati S 《Amino acids》2008,34(2):251-256
Summary. Previously published evidences highlighted the effect of transglutaminase (TG, EC 2.3.2.13) activation on the reduction of
the in vitro adhesive and invasive behaviour of murine B16-F10 melanoma cells, as well as in vivo. Here, we investigated the
influence of spermidine (SPD) incorporation by TG into basement membrane components i.e. laminin (LN) or Matrigel (MG), on
the adhesion and invasion of B16-F10 melanoma cells by these TG/SPD-modified substrates. The adhesion assays showed that cell
binding to the TG/SPD-modified LN was reduced by 30%, when compared to untreated LN, whereas the reduction obtained using
TG/SPD-modified MG was 35%. Similarly, tumor cell invasion by the Boyden chamber system through TG/SPD modified LN or MG was
respectively reduced by 45%, and by 69%. Evaluation of matrix metalloproteinase (gelatinases MMP-2 and MMP-9) activities by
gel-zymography showed that MMP-2 activity was unaffected, while MMP-9 activity was reduced by about 32% using TG/SPD-modified
substrate. These results strongly suggest that the observed antiinvasive effect of TG activation in the host may be ascribed
to the covalent incorporation of polyamines, which led to the post-translational modification of some components of the cell
basement membrane. This modification may interfere with the metastatic property of melanoma cells, affecting the proteolytic
activity necessary for their migration and invasion activities.
Authors’ address: Simone Beninati, Department of Biology, University of Rome “Tor Vergata”, Via della Ricerca Scientifica,
I-00133 Rome, Italy 相似文献
4.
Programmed cell death: similarities and differences in animals and plants. A flower paradigm 总被引:1,自引:0,他引:1
Summary. After an overview of the criteria for the definition of cell death in the animal cell and of its different types of death,
a comparative analysis of PCD in the plant cell is reported. The cytological characteristics of the plant cell undergoing
PCD are described.
The role of plant hormones and growth factors in the regulation of this event is discussed with particular emphasis on PCD
activation or prevention by polyamine treatment (doses, timing and developmental stage of the organism) in a Developmental
cell death plant model: the Nicotiana tabacum (tobacco) flower corolla. Some of the effects of polyamines might be mediated by transglutaminase catalysis. The activity
of this enzyme was examined in different parts of the corolla during its life span showing an acropetal trend parallel to
the cell death wave. The location of transglutaminase in some sub-cellular compartments suggests that it exerts different
functions in the corolla DCD. 相似文献
5.
6.
Mauro Piacentini Manuela D’Eletto Maria Grazia Farrace Carlo Rodolfo Franca Del Nonno Giuseppe Ippolito Laura Falasca 《Cell and tissue research》2014,358(3):793-805
Transglutaminase type II (TG2) is a pleiotropic enzyme that exhibits various activities unrelated to its originally identified functions. Apart from post-translational modifications of proteins (peculiar to the transglutaminase family enzymes), TG2 is involved in diverse biological functions, including cell death, signaling, cytoskeleton rearrangements, displaying enzymatic activities, G-protein and non-enzymatic biological functions. It is involved in a variety of human diseases such as celiac disease, diabetes, neurodegenerative diseases, inflammatory disorders and cancer. Regulatory mechanisms might exist through which cells control multifunctional protein expression as a function of their sub-cellular localization. The definition of the tissue and cellular distribution of such proteins is important for the determination of their function(s). We investigate the sub-cellular localization of TG2 by confocal and immunoelectron microscopy techniques in order to gain an understanding of its properties. The culture conditions of human sarcoma cells (2fTGH cells), human embryonic kidney cells (HEK293TG) and human neuroblastoma cells (SK-n-BE(2)) are modulated to induce various stimuli. Human tissue samples of myocardium and gut mucosa (diseased and healthy) are also analyzed. Immuno-gold labeling indicates that TG2 is localized in the nucleus, mitochondria and endoplasmic reticulum under physiological conditions but that this is not a stable association, since different locations or different amounts of TG2 can be observed depending on stress stimuli or the state of activity of the cell. We describe a possible unrecognized location of TG2. Our findings thus provide useful insights regarding the functions and regulation of this pleiotropic enzyme. 相似文献
7.
8.
Summary. Substance P (SP) is one of the most abundant peptides in the central nervous system and has been implicated in a variety of
physiological and pathophysiological processes including stress regulation, as well as affective and anxiety-related behaviour.
Consistent with these functions, SP and its preferred neurokinin 1 (NK1) receptor has been found within brain areas known
to be involved in the regulation of stress and anxiety responses. Aversive and stressful stimuli have been shown repeatedly
to change SP brain tissue content, as well as NK1 receptor binding. More recently it has been demonstrated that emotional
stressors increase SP efflux in specific limbic structures such as amygdala and septum and that the magnitude of this effect
depends on the severity of the stressor. Depending on the brain area, an increase in intracerebral SP concentration (mimicked
by SP microinjection) produces mainly anxiogenic-like responses in various behavioural tasks. Based on findings that SP transmission
is stimulated under stressful or anxiety-provoking situations it was hypothesised that blockade of NK1 receptors may attenuate
stress responses and exert anxiolytic-like effects. Preclinical and clinical studies have found evidence in favour of such
an assumption. The status of this research is reviewed here. 相似文献
9.
Tissue transglutaminase (TG2) activity has been implicated in inflammatory disease processes such as Celiac disease, infectious
diseases, cancer, and neurodegenerative diseases, such as Huntington’s disease. Furthermore, four distinct biochemical activities
have been described for TG2 including protein crosslinking via transamidation, GTPase, kinase and protein disulfide isomerase
activities. Although the enzyme plays a complex role in the regulation of cell death and autophagy, the molecular mechanisms
and the putative biochemical activity involved in each is unclear. Therefore, the goal of the present study was to determine
how TG2 modulates autophagy and/or apoptosis and which of its biochemical activities is involved in those processes. To address
this question, immortalized embryonic fibroblasts obtained from TG2 knock-out mice were reconstituted with either wild-type
TG2 or TG2 lacking its transamidating activity and these were subjected to different treatments to induce autophagy or apoptosis.
We found that knock out of the endogenous TG2 resulted in a significant exacerbation of caspase 3 activity and PARP cleavage
in MEF cells subjected to apoptotic stimuli. Interestingly, the same cells showed the accumulation of LC3 II isoform following
autophagy induction. These findings strongly suggest that TG2 transamidating activity plays a protective role in the response
of MEF cells to death stimuli, because the expression of the wild-type TG2, but not its transamidation inactive C277S mutant,
resulted in a suppression of caspase 3 as well as PARP cleavage upon apoptosis induction. Additionally, the same mutant was
unable to catalyze the final steps in autophagosome formation during autophagy. Our findings clearly indicate that the TG2
transamidating activity is the primary biochemical function involved in the physiological regulation of both apoptosis and
autophagy. These data also indicate that TG2 is a key regulator of cross-talk between autophagy and apoptosis. 相似文献
10.
Chemical-induced apoptotic cell death in tomato cells: involvement of caspase-like proteases 总被引:16,自引:0,他引:16
A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian
cells. This chemical-induced cell death was accompanied by the characteristic features of apoptosis in animal cells, such
as typical changes in nuclear morphology, the fragmentation of the nucleus and DNA fragmentation. In search of processes involved
in plant apoptotic cell death, specific enzyme inhibitors were tested for cell-death-inhibiting activity. Our results showed
that proteolysis plays a crucial role in apoptosis in plants. Furthermore, caspase-specific peptide inhibitors were found
to be potent inhibitors of the chemical-induced cell death in tomato cells, indicating that, as in animal systems, caspase-like
proteases are involved in the apoptotic cell death pathway in plants.
Received: 5 August 1999 / Accepted: 14 March 2000 相似文献
11.
Transglutaminase type 2 (TG2) is a ubiquitously expressed member of the transglutaminase family, capable of mediating a transamidation reaction between a variety of protein substrates. TG2 also has a unique role as a G-protein with GTPase activity. In response to GDP/GTP binding and increases in intracellular calcium levels, TG2 can undergo a large conformational change that reciprocally modulates the enzymatic activities of TG2. We have generated a TG2 biosensor that allows for quantitative assessment of TG2 conformational changes in live cells using Förster resonance energy transfer (FRET), as measured by fluorescence lifetime imaging microscopy (FLIM). Quantifying FRET efficiency with this biosensor provides a robust assay to quickly measure the effects of cell stress, changes in calcium levels, point mutations and chemical inhibitors on the conformation and localization of TG2 in living cells. The TG2 FRET biosensor was validated using established TG2 conformational point mutants, as well as cell stress events known to elevate intracellular calcium levels. We demonstrate in live cells that inhibitors of TG2 transamidation activity can differentially influence the conformation of the enzyme. The irreversible inhibitor of TG2, NC9, forces the enzyme into an open conformation, whereas the reversible inhibitor CP4d traps TG2 in the closed conformation. Thus, this biosensor provides new mechanistic insights into the action of two TG2 inhibitors and defines two new classes based on ability to alter TG2 conformation in addition to inhibiting transamidation activity. Future applications of this biosensor could be to discover small molecules that specifically alter TG2 conformation to affect GDP/GTP or calcium binding. 相似文献
12.
Role of osmoregulation in the actions of taurine 总被引:7,自引:0,他引:7
Summary. Taurine regulates an unusual number of biological phenomena, including heart rhythm, contractile function, blood pressure,
platelet aggregation, neuronal excitability, body temperature, learning, motor behavior, food consumption, eye sight, sperm
motility, cell proliferation and viability, energy metabolism and bile acid synthesis. Many of these actions are associated
with alterations in either ion transport or protein phosphorylation. Although the effects on ion transport have been attributed
to changes in membrane structure, they could be equally affected by a change in the activity of the affected transporters.
Three common ways of altering transporter activity is enhanced expression, changes in the phosphorylation status of the protein
and cytoskeletal changes. Interestingly, all three events are altered by osmotic stress. Since taurine is a key organic osmolyte
in most cells, the possibility that the effects of taurine on ion transport could be related to its osmoregulatory activity
was considered. This was accomplished by comparing the effects of taurine, cell swelling and cell shrinkage on the activities
of key ion channels and ion transporters. The review also compares the phosphorylation cascades initiated by osmotic stress
with some of the phosphorylation events triggered by taurine depletion or treatment. The data reveal that certain actions
of taurine are probably caused by the activation of osmotic-linked signaling pathways. Nonetheless, some of the actions of
taurine are unique and appear to be correlated with its membrane modulating and phosphorylation regulating activities.
Received January 25, 2000/Accepted January 31, 2000 相似文献
13.
Cho SY Jeong EM Lee JH Kim HJ Lim J Kim CW Shin DM Jeon JH Choi K Kim IG 《Molecules and cells》2012,33(3):235-241
The activation of transglutaminase 2 (TG2), an enzyme that catalyzes post-translational modifications of proteins, has been
implicated in apoptosis, cell adhesion and inflammatory responses. We previously reported that intracellular TG2 is activated
under oxidative stress conditions, such as ultraviolet irradiation, ischemia-reperfusion, and hypoxia. In this study, we examined
the effect of genotoxic stress on the intracellular activity of TG2 using doxorubicin which generates reactive oxygen species
that lead to double-strand breakage of DNA. We demonstrated that doxorubicin elicits the persistent activation of TG2. Doxorubicin-induced
TG2 activity was suppressed by treatment with caffeine at the early phase, N-acetylcysteine at the mid-phase, and EGTA at
the late phase. However, treatment with a blocking antibody against TGFβ or toll-like receptor 2 showed no effect on TG2 activity,
indicating that at least three different signaling pathways may be involved in the process of TG2 activation. In addition,
using MEF cells defective for TG2 and cells overexpressing an activesite mutant of TG2, we revealed that doxorubicin-induced
cell death is inversely correlated with TG2 activity. Our findings indicate that the persistent activation of TG2 by doxorubicin
contributes to cell survival, suggesting that the mechanism-based inhibition of TG2 may be a novel strategy to prevent drug-resistance
in doxorubicin treatment. 相似文献
14.
Marra M Agostinelli E Tempera G Lombardi A Meo G Budillon A Abbruzzese A Giuberti G Caraglia M 《Amino acids》2007,33(2):273-281
Summary. A correlation between regulation of cell proliferation and polyamine metabolism is described. The latter can enter protein
synthesis through the modification of eukaryotic initiation factor 5A (eIF5A) and the formation of the peculiar amino acid
hypusine. Specific inhibitors of hypusine formation induce apoptosis that can be potentiated by the combination with cytokines
such as interferonα (IFNα) that itself decreases hypusine synthesis. We have also demonstrated that the concomitant treatment
of cancer cells with IFNα and the protein synthesis inhibitor fusion protein TGFα/Pseudomonas Aeruginosa toxin synergize in inducing cancer cell growth inhibition. Another way used by polyamines to induce apoptosis is the generation
of intracellular oxidative stress through the interaction with bovine serum amine oxidase (BSAO). This enzyme used simultaneously
to spermine induces apoptosis, necrosis, inhibition of cell proliferation and inhibition of DNA and protein synthesis in several
cell types. The enzymatic oxidation products of polyamine, H2O2 and aldehyde(s) cause these effects. We have recently found that the cytotoxicity of anti-cancer agents, either etoposide
or docetaxel, in cancer cells is potentiated in the presence of BSAO/Spermine. In conclusion, polyamine metabolites could
be useful in the design of new therapeutic strategies. 相似文献
15.
Summary. Neurodegeneration induced by excitotoxicity is a common feature in various neurological disorders. This pathological condition is caused by prolonged stimulation of glutamate receptor subtypes, followed by both intracellular Ca2+ overload and activation of specific genes, resulting in synthesis of enzymes involved in cell stress response.Using experimental in vitro models of excitotoxicity, we demonstrated that glutamate exposure up-regulated tissue transglutaminase in primary cultures of both cerebellar granule cells and astrocytes. These changes were consequent to receptor-mediated Ca2+ influx, as demonstrated by the inhibition with selective antagonists, MK-801 and GYKI 52466. Early increases in different transglutaminase isoforms were also observed in global cerebral ischemia, which closely resembles neuronal damage caused by NMDA receptor activation.These findings agree with a postulated role for transglutaminases in molecular mechanisms of several neurodegenerative diseases. Indeed, increased cross-linking reactions could be of pathologic relevance, as part of biochemical changes observed in neurological disorders. 相似文献
16.
17.
Transglutaminase 2 (TG2) is a multifunctional calcium-dependent enzyme which catalyzes the post-translational protein crosslinking with formation of intra- or inter-molecular epsilon(gamma-glutamyl)lysine bonds or polyamine incorporation. The up-regulation and activation of TG2 have been reported in a variety of physiological events, including cell differentiation, signal transduction, apoptosis, and wound healing, as well as in cell response to stress evoked by different internal and external stimuli. Here we review TG2 role in cell response to redox state imbalance both under physiological and pathological conditions, such as neurodegenerative disorders, inflammation, autoimmune diseases and cataractogenesis, in which oxidative stress plays a pathogenetic role and also accelerates disease progression. The increase in TG activity together with mitochondrial impairment and collapse of antioxidant enzymatic cell defences have been reported to be the prominent biochemical alterations becoming evident prior to neurodegeneration. Moreover, oxidative stress-induced TG2 pathway is involved in autophagy inhibition and aggresome formation, and TG2 has been suggested to function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or proteasomal degradation. Literature data suggest a strong association between oxidative stress and TG2 up-regulation, which in turn may result in cell survival or apoptosis, depending on cell type, kind of stressor, duration of insult, as well as TG2 intracellular localization and activity state. In particular, it may be suggested that TG2 plays a pro-survival role when the alteration of cell redox state homeostasis is not associated with intracellular calcium increase triggering TG2 transamidation activity. 相似文献
18.
High levels of homocysteine promote cell damage mainly through induction of oxidative stress, endoplasmic reticulum (ER) stress,
and activation of pro-inflammatory factors. The effects of homocysteine were here examined in the continuously dividing neuroblastoma
cell line Neuro2a. Cell treatment with homocysteine (100–500 μM) for 4 h increased ROS production while reducing cell viability
in a dose-dependent manner. Cell exposure to 250 μM homocysteine was able to induce transglutaminase 2 up-regulation and increased
in situ transglutaminase activity. These effects were prevented by the incubation with the transglutaminase activity inhibitor
cystamine. Homocysteine also induced NF-κB activation that seemed associated with transglutaminase 2 up-regulation since the
specific NF-κB inhibition by SN50 was able to reduce transglutaminase expression and activity levels. In the light of these
observations, it may be postulated that TG2 up-regulation is involved in cell response to homocysteine-induced stress, in
which NF-κB activation plays also a pivotal role. 相似文献
19.
Tissue transglutaminase (TG2) is a Ca2+-dependent enzyme and probably the most ubiquitously expressed member of the mammalian transglutaminase family. TG2 plays a number of important roles in a variety of biological processes. Via its transamidating function, it is responsible for the cross-linking of proteins by forming isopeptide bonds between glutamine and lysine residues. Intracellularly, Ca2+ activation of the enzyme is normally tightly regulated by the binding of GTP. However, upregulated levels of TG2 are associated with many disease states like celiac sprue, certain types of cancer, fibrosis, cystic fibrosis, multiple sclerosis, Alzheimer’s, Huntington’s and Parkinson’s disease. Selective inhibitors for TG2 both cell penetrating and non-cell penetrating would therefore serve as novel therapeutic tools for the treatment of these disease states. Moreover, they would provide useful tools to fully elucidate the cellular mechanisms TG2 is involved in and help comprehend how the enzyme is regulated at the cellular level. The current paper is intended to give an update on the recently discovered classes of TG2 inhibitors along with their structure–activity relationships. The biological properties of these derivatives, in terms of both activity and selectivity, will also be reported in order to translate their potential for future therapeutic developments. 相似文献
20.
Because the H2O2 and O2
− generated during a pathogen-triggered oxidative burst could either protect or destroy a besieged plant cell, their synthesis
might be expected to be tightly regulated. We have examined the nature of this regulation as it is communicated between homologous
and heterologous oxidative-burst pathways, using both chemical (oligogalacturonic acid, harpin, fensulfothion) and mechanical
(osmotic stress) stimuli to induce the burst. We report here that the above three chemical elicitors attenuate a subsequent
oxidative burst induced in cultured soybean (Glycine max L.) cells by either the same (homologous desensitization) or a different chemical elicitor (heterologous desensitization).
Further, when the magnitude of the initial oxidative burst is maximal, the cells remain refractory to subsequent elicitation
for at least 10 min and then revive their sensitivities to re-stimulation with a half-time of >20 min. Mechanical stimulation
of the oxidative burst appears to be regulated by a different set of constraints. Although initiation of a mechanically induced
burst leads to attenuation of a subsequent mechanically induced burst, the same mechanical stimulus is peculiarly unable to
reduce a subsequent chemically induced burst. The converse is also true, suggesting that heterologous desensitization of the
oxidative burst does not extend to mixed chemical and mechanical/osmotic stimuli. However, communication between these disparate
forms of elicitation is still demonstrated to occur, since low-level chemical stimuli strongly synergize concurrent low-level
osmotic stimuli and vice versa. Furthermore, the pattern of synergy changes dramatically if one stimulus is administered immediately
prior to the other. Taken together, these data demonstrate that significant cross-talk occurs among the different signaling
pathways of the oxidative burst and that the overall process is tightly regulated.
Received: 10 January 2000 / Accepted: 22 February 2000 相似文献