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001-es BibID:BIBFORM005082
Első szerző:Detre, Cynthia
Cím:Death or survival : membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration / Detre, C., Kiss, E., Varga, Z., Ludanyi, K., Paszty, K., Enyedi, A., Kovesdi, D., Panyi, G., Rajnavolgyi, E., Matko, J.
Dátum:2006
ISSN:898-6568 (Print)
Megjegyzések:Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane of T-lymphocytes induced by different stimuli such as ligation of Fas/CD95, irradiation, stress, inflammation or anticancer drugs primarily involves mitochondrial apoptosis signaling, but under specific conditions non-apoptotic Fas-signaling was also reported. Here we investigated, using a quantitative simulation model with exogenous C2-ceramide (and SMase), the dependence of activation and fate of T-cells on the strength and duration of ceramide accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone or together with interacting antigen presenting B-cells (APC) was used. C2-ceramide induced apoptosis of TH cells above a 'threshold' stimulus (>25 microM in 'strength' or >30 min in duration), while below the threshold C2-ceramide was non-apoptotic, as confirmed by early and late apoptotic markers (PS-translocation, mitochondrial depolarization, caspase-3 activation, DNA-fragmentation). The modest ceramide stimuli strongly suppressed the calcium response and inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression or IL-2 production) in TH cells during both anti-CD3 induced and APC-triggered activation. Ceramide moderately affected the Ca2+ -release from internal stores upon antigen-specific engagement of TCR in immunological synapses, while the influx phase was remarkably reduced in both amplitude and rate, suggesting that the major target(s) of ceramide-effects are membrane-proximal. Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible. The impaired function of these transporters may be coupled to the quantitative, membrane raft-remodeling effect of ceramide and responsible, in a concerted action, for the suppressed activation. Our results suggest that non-apoptotic Fas stimuli, received from previously activated, FasL+ interacting lymphocytes in the lymph nodes, may negatively regulate subsequent antigen-specific T-cell activation and thus modulate the antigen-specific T-cell response.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
analogs and derivatives
Animals
Antigens,CD95
Apoptosis
B-Lymphocytes
Calcium
Caspase 3
Caspases
Cell Membrane
Cell Survival
Cells
DNA Fragmentation
Human
Humans
Hungary
immunology
Inflammation
Interleukin-2
Kv1.3 Potassium Channel
Lymph Nodes
Lymphocyte Activation
Lymphocytes
Membrane Potentials
metabolism
Mice
pharmacology
physiology
Potassium
Potassium Channels
Receptors,Antigen,T-Cell
Research
Signal Transduction
Sphingomyelin Phosphodiesterase
Sphingosine
Support
Synapses
T-Lymphocytes
T-Lymphocytes, Helper-Inducer
Time Factors
Megjelenés:Cellular Signalling. - 18 : 3 (2006), p. 294-306. -
További szerzők:Kiss Endre (Budapest) Varga Zoltán (1969-) (biofizikus, szakfordító) Ludányi Katalin (1975-) (immunológus) Pászty Katalin Enyedi Ágnes Kövesdi Dorottya Panyi György (1966-) (biofizikus) Rajnavölgyi Éva (1950-) (immunológus) Matkó János (1952-) (biológus)
Internet cím:elektronikus változat
DOI
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2.

001-es BibID:BIBFORM061401
Első szerző:Szöőr Árpád (orvos)
Cím:Cell confluence induces switching from proliferation to migratory signaling by site-selective phosphorylation of PDGF receptors on lipid raft platforms / Árpád Szöőr, László Ujlaky-Nagy, Gábor Tóth, János Szöllősi, György Vereb
Dátum:2016
ISSN:0898-6568
Megjegyzések:Platelet derived growth factor receptors (PDGFR) play an important role in tumor pathogenesis and are frequently overexpressed in glioblastoma. Earlier we have shown that only confluent glioblastoma cell cultures exhibit a biphasic calcium transient upon PDGF stimulation. Here, we examined how the change in cell density leads to differential cellular responses to the same PDGF stimulus. PDGF beta receptors and their specific phosphotyrosine residues were fluorescently colabeled on A172 and T98G glioblastoma cells. The distribution in cell membrane microdomains (lipid rafts) and the phosphorylation state of PDGFR was measured by confocal microscopy and quantitated by digital image processing. Corresponding bulk data were obtained by Western blotting. Activation of relevant downstream signaling pathways was assessed by immunofluorescence in confocal microscopy and by Western blot analysis. Functional outcomes were confirmed with bulk and single cell proliferation assays and motility measurements. In non-confluent (sparse) cultures PDGF-BB stimulation significantly increased phosphorylation of tyr716 specific for the Ras/MAPK pathway and tyr751 specific for the phosphoinositide 3-kinase/Akt pathway. As cell monolayers reached confluence, tyr771 and tyr1021 were the prominently phosphorylated residues. Tyr771 serves as adaptor for RasGAP, which inactivates the MAPK pathway, and tyr1021 feeds into the phospholipase Cgamma / PKC pathway. Coherent with this, MAPK phosphorylation, Ki67 positivity and proliferation dominated in dispersed cells, and could be abolished with inhibitors of the MAPK pathway. At the same time, RhoA activation, redistribution of cortactin to leading edges, and increased motility were the prominent output features in confluent cultures. Importantly, the stimulus-evoked confluence-specific changes in the phosphorylation of tyrosine residues occurred mainly in GM1-rich lipid microdomains (rafts). These observations suggest that the same stimulus is able to promote distinctly relevant signaling outputs through a confluence dependent, lipid raft-based regulatory mechanism. In particular, cell division and survival in sparse cultures and inhibition of proliferation and promotion of migration in confluent monolayers. In our model, the ability to switch the final output of the same stimulus as a function of cell density could be a key to the balance of proliferation and invasion in malignant glioblastoma.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
lipid rafts
site-selective phosphorylation
quantitative confocal microscopy
contact inhibition
tumor proliferation
invasive tumor growth
cell migration
glioblastoma
PDGFR
Megjelenés:Cellular Signalling. - 28 : 2 (2016), p. 81-93. -
További szerzők:Ujlaky-Nagy László (1977-) (biofizikus) Tóth Gábor (1989-) (általános orvos) Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
Pályázati támogatás:K75752
OTKA
NK 101337
OTKA
Baross Gabor Program
Egyéb
Internet cím:Szerző által megadott URL
DOI
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