The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
Edward J Goetzl - One of the best experts on this subject based on the ideXlab platform.
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lysophosphatidic acid and sphingosine 1 phosphate protection of t cells from apoptosis in association with suppression of bax
Journal of Immunology, 1999Co-Authors: Edward J Goetzl, Yvonne Kong, Baisong MeiAbstract:Members of a subfamily of G protein-coupled receptors (GPCRs), encoded by five different endothelial differentiation genes (edgs), specifically mediate effects of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) on cellular proliferation and differentiation. Mechanisms of suppression of apoptosis by LPA and S1P were studied in the Tsup-1 cultured line of human T Lymphoblastoma cells, which express Edg-2 and Edg-4 GPCRs for LPA and Edg-3 and Edg-5 GPCRs for S1P. At 10−10 M to 10−7 M, both LPA and S1P protected Tsup-1 cells from apoptosis induced by Abs to Fas, CD2, and CD3 plus CD28 in combination. Apoptosis elicited by C6 ceramide was inhibited by S1P, but not by LPA, in part because ceramide suppressed expression of Edg-2 and Edg-4 surface receptors for LPA without affecting Edg-3 surface receptors for S1P. At 10−9 M to 10−7 M, LPA and S1P significantly suppressed cellular levels of the apoptosis-promoting protein Bax, without altering the levels of Bcl-xL or Bcl-2 assessed by Western blots and immunoassays. Transfections of pairs of antisense plasmids for Edg-2 plus Edg-4 and Edg-3 plus Edg-5, and hygromycin selection of transfectants with reduced expression of the respective Edg R proteins in Western blots, inhibited both protection from apoptosis and reduction in cellular levels of Bax by LPA and S1P. Thus, LPA and S1P protection from apoptosis is mediated by distinct Edg GPCRs and may involve novel effects on Bax regulatory protein.
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predominant expression of type ii vasoactive intestinal peptide receptors by human t Lymphoblastoma cells transduction of both ca2 and cyclic amp signals
Journal of Clinical Immunology, 1996Co-Authors: Menghang Xia, Sunil P Sreedharan, Edward J GoetzlAbstract:An immunoregulatory role for vasoactive intestinal peptide (VIP) is suggested by the high concentrations in subsets of neurons supplying lymphoid organs and by the capacity of VIP to affect T lymphocyte functions. The Tsup-1 line of human T Lymphoblastoma cells expresses both type I and type II G protein-coupled VIP receptors (Rs), as shown by detection of the encoding mRNAs with reverse transcription-polymerase chain reaction analyses. Northern blot quantification of the relative amounts of mRNA encoding the two VIPRs in Tsup-1 cells indicated that type II predominates over type I, as it does in human blood CD4+ T cells. Tsup-1 cells bound125I-VIP to 8.95×104 high-affinity sites/cell (Kd=6.0 nM) and 7.45× 105 low-affinity sites/cell (Kd=210 nM). VIP increased [cAMP]i in Tsup-1 cells (EC50=14.4 nM) and stimulated a rapid and transient increase in [Ca2+]i (EC50=30 nM). Functional coupling of G proteins to type II VIPRs was suggested by the change in binding of125I-VIP to Tsup-1 cell membranes from two sites with Kd values of 3.8 and 109 nM to one site ofKd 30 nM by GTP-γ-S and the suppression by pertussis toxin of increases in [Ca2+]i evoked by VIP. The VIP antagonists, VIP4–28 and (4-Cl-D-Phe6-Leu17) VIP, inhibited125I-VIP binding by type II VIPRs, as well as VIP-elicited increases in [Ca2+]i and [cAMP]i. Type II VIPRs thus are the major transducers of VIP signals to a subset of human T cells.
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stimulation of matrix metalloproteinase dependent migration of t cells by eicosanoids
The FASEB Journal, 1995Co-Authors: David Leppert, Stephen L Hauser, Jeffrey L Kishiyama, Li Zeng, Edward J GoetzlAbstract:Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), at nanomolar to micromolar concentrations, elicited migration of human blood T cells and cultured T Lymphoblastoma cells of the Tsup-1 line through a layer of Matrigel basement membrane matrix. The density of Tsup-1 cell high-affinity receptors was low for PGE2 and high for LTB4, resulting in respectively predominant chemokinetic and chemotactic stimulation of migration. Migration-enhancing concentrations of PGE2 and LTB4 also increased Tsup-1 cell content and secretion of matrix metalloproteinases (MMPs) 2, 3, and 9, which were quantified by Western blots and zymography, and augmented Tsup-1 cell-surface expression of the MMPs, as shown by flow cytometry. That a specific MMP inhibitor suppressed migration of blood T cells and Tsup-1 cells through Matrigel, but did not affect PGE2- and LTB4-initiated T cell migration through micropore filters without Matrigel, suggests dual requirements for MMP expression and enhanced motility in T cell passage through basement membranes.
Zoltan Szallasi - One of the best experts on this subject based on the ideXlab platform.
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Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts.
British journal of cancer, 2018Co-Authors: Ádám Póti, Yonghong Xiao, Keith Mikule, Keith Wilcoxen, Kinga Berta, Orsolya Pipek, Gregory T. Klus, Thomas Ried, István Csabai, Zoltan SzallasiAbstract:Poly-ADP ribose polymerase (PARP) inhibitor-based cancer therapy selectively targets cells with deficient homologous recombination repair. Considering their long-term use in maintenance treatment, any potential mutagenic effect of PARP inhibitor treatment could accelerate the development of resistance or harm non-malignant somatic cells. We tested the mutagenicity of long-term treatment with the PARP inhibitor niraparib using whole-genome sequencing of cultured cell clones and whole-exome sequencing of patient-derived breast cancer xenografts. We observed no significant increase in the number and alteration in the spectrum of base substitutions, short insertions and deletions and genomic rearrangements upon niraparib treatment of human DLD-1 colon adenocarcinoma cells, wild-type and BRCA1 mutant chicken DT40 Lymphoblastoma cells and BRCA1-defective SUM149PT breast carcinoma cells, except for a minor increase in specific deletion classes. We also did not detect any contribution of in vivo niraparib treatment to subclonal mutations arising in breast cancer-derived xenografts. The results suggest that long-term inhibition of DNA repair with PARP inhibitors has no or only limited mutagenic effect. Mutagenesis due to prolonged use of PARP inhibitors in cancer treatment is therefore not expected to contribute to the genetic evolution of resistance, generate significant immunogenic neoepitopes or induce secondary malignancies.
James P Mcnamee - One of the best experts on this subject based on the ideXlab platform.
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gene expression analysis of a human Lymphoblastoma cell line exposed in vitro to an intermittent 1 9 ghz pulse modulated radiofrequency field
Radiation Research, 2006Co-Authors: Vinita Chauhan, A Mariampillai, P V Bellier, Sami S Qutob, G B Gajda, E Lemay, A Thansandote, James P McnameeAbstract:Abstract Chauhan, V., Mariampillai, A., Bellier, P. V., Qutob, S. S., Gajda, G. B., Lemay, E., Thansandote, A. and McNamee, J. P. Gene Expression Analysis of a Human Lymphoblastoma Cell Line Exposed In Vitro to an Intermittent 1.9 GHz Pulse-Modulated Radiofrequency Field. Radiat. Res. 165, 424–429 (2006). This study was designed to determine whether radiofrequency (RF) fields of the type used for wireless communications could elicit a cellular stress response. As general indicators of a cellular stress response, we monitored changes in proto-oncogene and heat-shock protein expression. Exponentially growing human Lymphoblastoma cells (TK6) were exposed to 1.9 GHz pulse-modulated RF fields at average specific absorption rates (SARs) of 1 and 10 W/kg. Perturbations in the expression levels of the proto-oncogenes FOS, JUN and MYC after exposure to sham and RF fields were assessed by real-time RT-PCR. In addition, the transcript levels of the cellular stress proteins HSP27 and inducible HSP70 were also monitor...
Szuts D. - One of the best experts on this subject based on the ideXlab platform.
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A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance.
'Elsevier BV', 2017Co-Authors: Gervai J., Galicza J., Szeltner Z., Zamborszky J., Szuts D.Abstract:Post-translational modifications of Proliferating Cell Nuclear Antigen (PCNA) play a key role in regulating the bypass of DNA lesions during DNA replication. PCNA can be monoubiquitylated at lysine 164 by the RAD6-RAD18 ubiquitin ligase complex. Through this modification, PCNA can interact with low fidelity Y family DNA polymerases to promote translesion synthesis. Monoubiquitylated PCNA can be polyubiquitylated on lysine 63 of ubiquitin by a further ubiquitin-conjugating complex. This modification promotes a template switching bypass process in yeast, while its role in higher eukaryotes is less clear. We investigated the function of PCNA ubiquitylation using a PCNA(K164R) mutant DT40 chicken B Lymphoblastoma cell line, which is hypersensitive to DNA damaging agents such as methyl methanesulfonate (MMS), cisplatin or ultraviolet radiation (UV) due to the loss of PCNA modifications. In the PCNA(K164R) mutant we also detected cell cycle arrest following UV treatment, a reduced rate of damage bypass through translesion DNA synthesis on synthetic UV photoproducts, and an increased rate of genomic mutagenesis following MMS treatment. PCNA-ubiquitin fusion proteins have been reported to mimic endogenous PCNA ubiquitylation. We found that the stable expression of a PCNA(K164R)-ubiquitin fusion protein fully or partially rescued the observed defects of the PCNA(K164R) mutant. The expression of a PCNA(K164R)-ubiquitin(K63R) fusion protein, on which the formation of lysine 63-linked polyubiquitin chains is not possible, similarly rescued the cell cycle arrest, DNA damage sensitivity, reduction of translesion synthesis and increase of MMS-induced genomic mutagenesis. Template switching bypass was not affected by the genetic elimination of PCNA polyubiquitylation, but it was reduced in the absence of the recombination proteins BRCA1 or XRCC3. Our study found no requirement for PCNA polyubiquitylation to protect cells from replication-stalling DNA damage
Szüts Dávid - One of the best experts on this subject based on the ideXlab platform.
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A genetic study based on PCNA-ubiquitin fusions reveals no requirement for PCNA polyubiquitylation in DNA damage tolerance
'Elsevier BV', 2017Co-Authors: Gervai, Judit Zsuzsanna, Gálicza Judit, Szeltner Zoltán, Zámborszky Judit, Szüts DávidAbstract:Post-translational modifications of Proliferating Cell Nuclear Antigen (PCNA) play a key role in regulating the bypass of DNA lesions during DNA replication. PCNA can be monoubiquitylated at lysine 164 by the RAD6-RAD18 ubiquitin ligase complex. Through this modification, PCNA can interact with low fidelity Y family DNA polymerases to promote translesion synthesis. Monoubiquitylated PCNA can be polyubiquitylated on lysine 63 of ubiquitin by a further ubiquitin-conjugating complex. This modification promotes a template switching bypass process in yeast, while its role in higher eukaryotes is less clear. We investigated the function of PCNA ubiquitylation using a PCNAK164R mutant DT40 chicken B Lymphoblastoma cell line, which is hypersensitive to DNA damaging agents such as methyl methanesulfonate (MMS), cisplatin or ultraviolet radiation (UV) due to the loss of PCNA modifications. In the PCNAK164R mutant we also detected cell cycle arrest following UV treatment, a reduced rate of damage bypass through translesion DNA synthesis on synthetic UV photoproducts, and an increased rate of genomic mutagenesis following MMS treatment. PCNA-ubiquitin fusion proteins have been reported to mimic endogenous PCNA ubiquitylation. We found that the stable expression of a PCNAK164R-ubiquitin fusion protein fully or partially rescued the observed defects of the PCNAK164R mutant. The expression of a PCNAK164R-ubiquitinK63R fusion protein, on which the formation of lysine 63-linked polyubiquitin chains is not possible, similarly rescued the cell cycle arrest, DNA damage sensitivity, reduction of translesion synthesis and increase of MMS-induced genomic mutagenesis. Template switching bypass was not affected by the genetic elimination of PCNA polyubiquitylation, but it was reduced in the absence of the recombination proteins BRCA1 or XRCC3. Our study found no requirement for PCNA polyubiquitylation to protect cells from replication-stalling DNA damage. © 2017 Elsevier B.V
