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001-es BibID:BIBFORM112979
035-os BibID:(cikkazonosító)10938 (WoS)001028670900001 (Scopus)85165107467
Első szerző:Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2 / Károly Jambrovics, Szilárd Póliska, Beáta Scholtz, Iván P. Uray, Zoltán Balajthy
Dátum:2023
ISSN:1422-0067
Megjegyzések:Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:International Journal Of Molecular Sciences. - 24 : 13 (2023), p. 1-11. -
További szerzők:Póliska Szilárd (1978-) (biológus) Scholtz Beáta (1967-) (biokémikus, molekuláris biológus) Uray Iván Péter (1970-) (kutatóorvos) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:129139
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2.

001-es BibID:BIBFORM110245
035-os BibID:(cikkazonosító)217 (Scopus)85151110056 (WoS)000962544000005
Első szerző:Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:Transglutaminase 2 associated with PI3K and PTEN in a membrane-bound signalosome platform blunts cell death / Jambrovics Károly, Botó Pál, Pap Attila, Sarang Zsolt, Kolostyák Zsuzsanna, Czimmerer Zsolt, Szatmari Istvan, Fésüs László, Uray Iván P., Balajthy Zoltán
Dátum:2023
ISSN:2041-4889
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Cell Death & Disease. - 14 : 3 (2023), p. 1-10. -
További szerzők:Botó Pál (1986-) (molekuláris biológus) Pap Attila (1980-) (biológus) Sarang Zsolt (1976-) (mikrobiológus) Kolostyák Zsuzsanna Czimmerer Zsolt (1981-) (molekuláris biológus) Szatmári István (1971-) (biológus) Fésüs László (1947-) (orvos biokémikus) Uray Iván Péter (1970-) (kutatóorvos) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:K129139
OTKA
K129218
OTKA
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3.

001-es BibID:BIBFORM107571
Első szerző:Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:ATRA and ATO combination has several beneficial effects in treatment of Acute Promyelocytic Leukaemia cells / Jambrovics Károly, Balajthy Zoltán
Dátum:2022
Megjegyzések:All-trans-retinoic acid (ATRA) therapy is one of the most frequently used therapy to treat acute promyelocyte leukaemia (APL) inducing terminal differentiation towards neutrophil granulocytes. Arsenic-trioxide (ATO) and ATRA and ATO combined treatments had been identified as another effective treatment in the late 90s' and then it was subsequently proved that this therapy can trigger both inductions of apoptosis and attenuation the inflammatory cytokine/chemokine production in vitro [Jambrovics et al., Cancer 2020]. Combined treatments can prolong the survival of APL patients in a dose-dependent manner by activation of the cellular signalling pathways leading to, among others, an enhanced reactive oxygen species (ROS) generation by the NADPH-oxidase system. ATO alone induces partial differentiation and apoptosis, leading to the remission in relapsed APL patients with the initiation of the degradation of the PML-RAR? oncoprotein. ATRA and ATO combined treatments result in up and down-regulation of more than a thousand genes to generate functional neutrophil granulocytes. One of the most up-regulated genes in ATRA induced differentiation of NB4 APL cell line is the tissue transglutaminase (TG2). Silencing and knocking out of TG2 expression in NB4 cells revealed that TG2 is required for adhesion, migratory, the phagocytic capacity of neutrophils, superoxide (ROS) production and inflammatory cytokine/chemokine production [Balajthy et al., Blood 2006, Jambrovics et al., Haematologica 2018, Jambrovics et al., Cancer 2020]. To investigate the role of TG2 further, NB4 cell lines were treated with ATRA + ATO in two different combinations, where we found that without the TG2, NB4 cells were more sensitive to the arsenic-induced apoptosis. Additionally, we observed that the apoptosis induction by arsenic resulted in a degradation of the TG2 protein.
Tárgyszavak:Orvostudományok Elméleti orvostudományok előadáskivonat
könyvrészlet
Megjelenés:15th Molecular, Cell and Immune Biology Winter Symposium : Book of abstract. - p. 25
További szerzők:Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
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4.

001-es BibID:BIBFORM084074
035-os BibID:(cikkazonosító)648 (WoS)000530232300124 (Scopus)85081217936
Első szerző:Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2 / Jambrovics Károly, Uray Iván P., Keillor Jeffrey W., Fésüs László, Balajthy Zoltán
Dátum:2020
ISSN:2072-6694
Megjegyzések:Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1?] and tumor necrosis factor-? [TNF-?]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expressiondependent manner. The amount of secreted TNF-? in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1? and TNF-? 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Cancers. - 12 : 3 (2020), p. 648-. -
További szerzők:Uray Iván Péter (1970-) (kutatóorvos) Keillor, Jeffrey W. Fésüs László (1947-) (orvos biokémikus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00020
GINOP
K129218
OTKA
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5.

001-es BibID:BIBFORM077169
035-os BibID:(WoS)000460110400026 (Scopus)85063936796
Első szerző:Jambrovics Károly (biológus, gyógyszer-biotechnológus)
Cím:Transglutaminase 2 programs differentiating acute promyelocytic leukemia cells in all-trans retinoic acid treatment to inflammatory stage through NF-kB activation / Jambrovics Károly, Uray Iván P., Keresztessy Zsolt, Keillor Jeffrey W., Fésüs László, Balajthy Zoltán
Dátum:2019
ISSN:0390-6078
Megjegyzések:Differentiation syndrome is a life-threatening complication arising during retinoid treatment of acute promyelocytic leukemia. Administration of all-trans retinoic acid leads to significant changes in gene expression, among the most induced of which is transglutaminase 2, which is not normally expressed in neutrophil granulocytes. To evaluate the pathophysiological function of transglutaminase 2 in the context of immunological function and disease outcomes, such as excessive superoxide anion, cytokine, and chemokine production in differentiated NB4 cells, we used an NB4 transglutaminase knock-out cell line and a transglutaminase inhibitor, NC9, which inhibits both transamidase- and guanosine triphosphate-binding activities, to clarify transglutaminase's contribution to the development of potentially lethal differentiation syndrome during all-trans retinoic acid treatment of acute promyelocytic leukemia. We found that such treatment not only enhanced cell-surface expression of CD11b and CD11c but also induced high-affinity states; atypical transglutaminase 2 expression in NB4 cells activated the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, driving pathogenic processes with an inflammatory cascade through the expression of numerous cytokines, including Tumor necrosis factor alpha, Interleukin 1 beta, and Monocyte chemoattractant protein 1. NC9 decreased the amount of transglutaminase 2, p65/RelA, and p50 in differentiated NB4 cells and their nuclei, leading to attenuated inflammatory cytokine synthesis. NC9 significantly inhibits transglutaminase 2 nuclear translocation but accelerates its proteasomal breakdown. This study demonstrates that transglutaminase 2 expression induced by all-trans retinoic acid treatment reprograms inflammatory signaling networks governed by nuclear factor kappa-light-chain-enhancer of activated B cells activation, resulting in over-expression of tumor necrosis factor alpha and Interleukin 1 beta in differentiating acute promyelocytic leukemia cells, suggesting that atypically expressed transglutaminase 2 is a promising target for leukemia treatment.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Haematologica-The Hematology Journal. - 104 : 3 (2019), p. 505-515. -
További szerzők:Uray Iván Péter (1970-) (kutatóorvos) Keresztessy Zsolt Keillor, Jeffrey W. Fésüs László (1947-) (orvos biokémikus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00020
GINOP
TÁMOP-4.2.2.D-15/1/KONV-2015-0016
TÁMOP
EFOP-3.6.1-16-2016-00022
EFOP
GINOP-2.3.2-15-2016-00006
GINOP
NK105046
OTKA
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6.

001-es BibID:BIBFORM097487
Első szerző:Kenesei Ádám
Cím:IL-15 Trans-Presentation Is an Autonomous, Antigen-Independent Process / Kenesei Ádám, Volkó Julianna, Szalóki Nikoletta, Mocsár Gábor, Jambrovics Károly, Balajthy Zoltán, Bodnár Andrea, Tóth Katalin, Waldmann Thomas A., Vámosi György
Dátum:2021
ISSN:0022-1767 1550-6606
Megjegyzések:IL-15 plays a pivotal role in the long-term survival of T cells and immunological memory. Its receptor consists of three subunits (IL-15R?, IL-2/15R?, and ?c). IL-15 functions mainly via trans-presentation (TP), during which an APC expressing IL-15 bound to IL-15R? presents the ligand to the ??c receptor-heterodimer on a neighboring T/NK cell. To date, no direct biophysical evidence for the intercellular assembly of the IL-15R heterotrimer exists. Ag presentation (AP), the initial step of T cell activation, is also based on APC?T cell interaction. We were compelled to ask whether AP has any effect on IL-15 TP or whether they are independent processes. In our human Raji B cell?Jurkat T cell model system, we monitored inter-/intracellular protein interactions upon formation of IL-15 TP and AP receptor complexes by Förster resonance energy transfer measurements. We detected enrichment of IL-15R? and IL-2/15R? at the synapse and positive Förster resonance energy transfer efficiency if Raji cells were pretreated with IL-15, giving direct biophysical evidence for IL-15 TP. IL-15R? and MHC class II interacted and translocated jointly to the immunological synapse when either ligand was present, whereas IL-2/15R? and CD3 moved independently of each other. IL-15 TP initiated STAT5 phosphorylation in Jurkat cells, which was not further enhanced by AP. Conversely, IL-15 treatment slightly attenuated Ag-induced phosphorylation of the CD3? chain. Our studies prove that in our model system, IL-15 TP and AP can occur independently, and although AP enhances IL-15R assembly, it has no significant effect on IL-15 signaling during TP. Thus, IL-15 TP can be considered an autonomous, Ag-independent process.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
interleukin
trans-presentation
immunology
Megjelenés:Journal Of Immunology. - 207 : 10 (2021), p. 2489-2500. -
További szerzők:Volkó Julianna (1983-) (biotechnológus) Szalóki Nikoletta (1981-) (biológus) Mocsár Gábor (1981-) (biofizikus) Jambrovics Károly (1988-) (biológus, gyógyszer-biotechnológus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus) Dóczy-Bodnár Andrea (1970-) (biofizikus) Tóth Katalin Ágnes (1977-) (biokémikus, molekuláris biológus) Waldmann, Thomas A. Vámosi György (1967-) (biofizikus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00026
GINOP
EFOP-3.6.3-VEKOP-16-2017-00009
EFOP
Tempus Public Foundation 273478
Egyéb
Deutscher Akademischer Austauschdienst 273478
Egyéb
HHS | NIH | National Cancer Institute intramural research program
Egyéb
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7.

001-es BibID:BIBFORM081020
035-os BibID:(WoS)000490183000049 (Scopus)85073312410
Első szerző:Volkó Julianna (biotechnológus)
Cím:IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti-IL-2R[alfa] therapies / Volkó Julianna, Kenesei Ádám, Zhang Meili, Várnai Péter, Mocsár Gábor, Petrus Michael N., Jambrovics Károly, Balajthy Zoltán, Müller Gabriele, Bodnár Andrea, Tóth Katalin, Waldmann Thomas A., Vámosi György
Dátum:2019
ISSN:0027-8424 1091-6490
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Proceedings Of The National Academy Of Sciences Of The United States Of America. - 116 : 42 (2019), p. 21120-21130. -
További szerzők:Kenesei Ádám (1989-) Zhang, Meili Várnai Péter Mocsár Gábor (1981-) (biofizikus) Petrus, Michael N. Jambrovics Károly (1988-) (biológus, gyógyszer-biotechnológus) Balajthy Zoltán (1957-) (biokémikus, sejtbiológus) Müller, Gabriele Dóczy-Bodnár Andrea (1970-) (biofizikus) Tóth Katalin (biofizikus) Waldmann, Thomas A. Vámosi György (1967-) (biofizikus)
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