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1.
Khder H. Rasul Alamdar Hussain Hazel Reilly Maria Karvouni Carin I. M. Dahlberg Mustafa S. Al-Attar Arnika K. Wagner Evren Alici Dara K. Mohammad 《Current issues in molecular biology》2022,44(9):3859
Among the polypeptides that comprise the T cell receptor (TCR), only CD3ζ is found in Natural Killer (NK) cells, where it transmits signals from activating receptors such as CD16 and NKp46. NK cells are potent immune cells that recognize target cells through germline-encoded activating and inhibitory receptors. Genetic engineering of NK cells enables tumor-specific antigen recognition and, thus, has a significant promise in adoptive cell therapy. Ectopic expression of engineered TCR components in T cells leads to mispairing with the endogenous components, making a knockout of the endogenous TCR necessary. To circumvent the mispairing of TCRs or the need for knockout technologies, TCR complex expression has been studied in NK cells. In the current study, we explored the cellular processing of the TCR complex in NK cells. We observed that in the absence of CD3 subunits, the TCR was not expressed on the surface of NK cells and vice versa. Moreover, a progressive increase in surface expression of TCR between day three and day seven was observed after transduction. Interestingly, the TCR complex expression in NK92 cells was enhanced with a proteasome inhibitor (bortezomib) but not a lysosomal inhibitor (chloroquine). Additionally, we observed that the TCR complex was functional in NK92 cells as measured by estimating CD107a as a degranulation marker, IFNγ cytokine production, and killing assays. NK92 cells strongly degranulated when CD3ε was engaged in the presence of TCR, but not when only CD3 was overexpressed. Therefore, our findings encourage further investigation to unravel the mechanisms that prevent the surface expression of the TCR complex. 相似文献
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Genead R Fischer H Hussain A Jaksch M Andersson AB Ljung K Bulatovic I Franco-Cereceda A Elsheikh E Corbascio M Smith CI Sylvén C Grinnemo KH 《PloS one》2012,7(5):e36804
To explore how cardiac regeneration and cell turnover adapts to disease, different forms of stress were studied for their effects on the cardiac progenitor cell markers c-Kit and Isl1, the early cardiomyocyte marker Nkx2.5, and mast cells. Adult female rats were examined during pregnancy, after myocardial infarction and ischemia-reperfusion injury with/out insulin like growth factor-1(IGF-1) and hepatocyte growth factor (HGF). Different cardiac sub-domains were analyzed at one and two weeks post-intervention, both at the mRNA and protein levels. While pregnancy and myocardial infarction up-regulated Nkx2.5 and c-Kit (adjusted for mast cell activation), ischemia-reperfusion injury induced the strongest up-regulation which occurred globally throughout the entire heart and not just around the site of injury. This response seems to be partly mediated by increased endogenous production of IGF-1 and HGF. Contrary to c-Kit, Isl1 was not up-regulated by pregnancy or myocardial infarction while ischemia-reperfusion injury induced not a global but a focal up-regulation in the outflow tract and also in the peri-ischemic region, correlating with the up-regulation of endogenous IGF-1. The addition of IGF-1 and HGF did boost the endogenous expression of IGF and HGF correlating to focal up-regulation of Isl1. c-Kit expression was not further influenced by the exogenous growth factors. This indicates that there is a spatial mismatch between on one hand c-Kit and Nkx2.5 expression and on the other hand Isl1 expression. In conclusion, ischemia-reperfusion injury was the strongest stimulus with both global and focal cardiomyocyte progenitor cell marker up-regulations, correlating to the endogenous up-regulation of the growth factors IGF-1 and HGF. Also pregnancy induced a general up-regulation of c-Kit and early Nkx2.5+ cardiomyocytes throughout the heart. Utilization of these pathways could provide new strategies for the treatment of cardiac disease. 相似文献
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First and second half-wave reduction potentials of 11 1,4-naphthoquinones and 42 9,10-anthraquinones have been measured for solutions in dimethylformamide. The presence of hydroxy groups at the 5- and 8-positions of the 1,4-naphthoquinone nucleus, and at the 1-, 4-, 5- and 8-positions of the 9,10-anthraquinone (the alpha-positions) markedly raises both reduction potentials. Measurements on the corresponding methoxy- and acetoxyquinones indicate that internal hydrogen bonding in the alpha-hydroxyquinones makes a major contribution to stabilisation of the semiquinone, probably as a result of increased delocalisation due to exchange of the hydroxy hydrogen between the two neighbouring oxygen atoms. The bearing of this phenomenon on the mechanism of action of anthracycline antitumour quinones is discussed, and the stabilising effect on the semiquinone of hydroxy groups at the 1- and 5-positions of the 9,10-anthraquinone nucleus is highlighted. 相似文献
4.
Alamdar Hussain Dara K. Mohammad Manuela O. Gustafsson Merve Uslu Abdulrahman Hamasy Beston F. Nore Abdalla J. Mohamed C. I. Edvard Smith 《The Journal of biological chemistry》2013,288(10):7338-7350
The inducible T cell kinase-spleen tyrosine kinase (ITK-SYK) oncogene consists of the Tec homology-pleckstrin homology domain of ITK and the kinase domain of SYK, and it is believed to be the cause of peripheral T cell lymphoma. We and others have recently demonstrated that this fusion protein is constitutively tyrosine-phosphorylated and is transforming both in vitro and in vivo. To gain a deeper insight into the molecular mechanism(s) underlying its activation and signaling, we mutated a total of eight tyrosines located in the SYK portion of the chimera into either phenylalanine or to the negatively charged glutamic acid. Although mutations in the interdomain-B region affected ITK-SYK kinase activity, they only modestly altered downstream signaling events. In contrast, mutations that were introduced in the kinase domain triggered severe impairment of downstream signaling. Moreover, we show here that SLP-76 is critical for ITK-SYK activation and is particularly required for the ITK-SYK-dependent phosphorylation of SYK activation loop tyrosines. In Jurkat cell lines, we demonstrate that expression of ITK-SYK fusion requires an intact SLP-76 function and significantly induces IL-2 secretion and CD69 expression. Furthermore, the SLP-76-mediated induction of IL-2 and CD69 could be further enhanced by SYK or ZAP-70, but it was independent of their kinase activity. Notably, ITK-SYK expression in SYF cells phosphorylates SLP-76 in the absence of SRC family kinases. Altogether, our data suggest that ITK-SYK exists in the active conformation state and is therefore capable of signaling without SRC family kinases or stimulation of the T cell receptor. 相似文献
5.
Studies have indicated that systolic (SBP) and diastolic (DBP) blood pressure are multi-factorial traits and significantly heritable. The aims of the present study are to assess whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genotypes are associated with SBP and DBP of normotensive subjects and to ascertain whether the level of SBP and DBP given exposure to cigarette smoking is modified by the specific genetic polymorphisms of GSTM1 and GSTT1. This cross-sectional study was conducted on 140 subjects (49 females and 91 males) (mean age+/-SD: 38.7+/-14.7). The genotypes were determined using a polymerase chain reaction based method. Individuals were stratified according to the mean values of DBP and SBP, lower than or maximally same as the mean value defines as group I and higher than the mean value defines as group II. The logistic regression analyses were used. The best models fitted by logistic regression analysis for variables were associated with SBP and DBP. For analysis the combination of genotypes, sex, and smoking behavior was used as qualitative variables, and age, body mass index (BMI), and heart rate were used as covariates. Combination of "present-GSTT1, null-GSTM1" genotype (OR=0.001, 95% CI=0.00-0.439, P=0.025), heart rate (OR=1.065, 95% CI=1.018-1.114, P=0.006), and interaction between BMI and combination of "present-GSTT1, null-GSTM1" (OR=1.319, 95% CI=1.058-1.644, P=0.014) was associated with SBP. There was no association between either combination genotypes of GSTs or interaction of genotypes and smoking behavior on DBP. The present results suggest that the GSTM1 gene is one of the candidate genes that alter the baseline of SBP in normotensive individuals. 相似文献
6.
Alamdar Ashnagar J.Malcolm Bruce P.Leslie Dutton Roger C. Prince 《Biochimica et Biophysica Acta (BBA)/General Subjects》1984,801(3):351-359
First and second half-wave reduction potentials of 11 1,4-naphthoquinones and 42 9,10-anthraquinones have been measured for solutions in dimethylformamide. The presence of hydroxy groups at the 5- and 8-positions of the 1,4-naphthoquinone nucleus, and at the 1-, 4-, 5- and 8-positions of the 9,10-anthraquinone (the α-positions) markedley raises both reduction potentials. Measurements on the corresponding methoxy- and acetoxyquinones indicate that internal hydrogen bonding in the α-hydroxyquinones makes a major contribution to stabilisation of the semiquinone, probably as a result of increased delocalisation due to exchange of the hydroxy hydrogen between the two neighbouring oxygen atoms. The bearing of this phenomenon on the mechanism of action off anthracycline antitumour quinones is discussed, and the stabilising effect on the semiquinone of hydroxy groups at the 1- adn 5-positions of the 9,10-anthraquinone nucleus is highlighted. 相似文献
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The TEC family is ancient and constitutes the second largest family of cytoplasmic tyrosine kinases. In 1993, loss-of-function mutations in the BTK gene were reported as the cause of X-linked agammaglobulinemia. Of all the existing 90 tyrosine kinases in humans, Bruton's tyrosine kinase (BTK) is the kinase for which most mutations have been identified. These experiments of nature collectively provide a form of mutation scanning with direct implications for the several hundred endogenous signaling proteins carrying domains also found in BTK. In 2009, an inactivating mutation in the ITK gene was shown to cause susceptibility to lethal Epstein-Barr virus infection. Both kinases represent interesting targets for inhibition: in the case of BTK, as an immunosuppressant, whereas there is evidence that the inhibition of inducible T-cell kinase (ITK) could influence the infectivity of HIV and also have anti-inflammatory activity. Since 2006, several patients carrying a fusion protein, originating from a translocation joining genes encoding the kinases ITK and spleen tyrosine kinase (SYK), have been shown to develop T-cell lymphoma. We review these disease processes and also describe the role of the N-terminal pleckstrin homology-Tec homology (PH-TH) domain doublet of BTK and ITK in the downstream intracellular signaling of such fusion proteins. 相似文献
10.
Dara K. Mohammad Beston F. Nore Alamdar Hussain Manuela O. Gustafsson Abdalla J. Mohamed C. I. Edvard Smith 《Molecular and cellular biology》2013,33(16):3214-3226
Bruton''s tyrosine kinase (Btk) is crucial for B-lymphocyte activation and development. Mutations in the Btk gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Using tandem mass spectrometry, 14-3-3ζ was identified as a new binding partner and negative regulator of Btk in both B-cell lines and primary B lymphocytes. The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. The double-alanine, S51A/T495A, replacement mutant failed to bind 14-3-3ζ, while phosphomimetic aspartate substitutions, S51D/T495D, caused enhanced interaction. The phosphatidylinositol 3-kinase (PI3-kinase) inhibitor abrogated S51/T495 phosphorylation and binding. A newly characterized 14-3-3 inhibitor, BV02, reduced binding, as did the Btk inhibitor PCI-32765 (ibrutinib). Interestingly, in the presence of BV02, phosphorylation of Btk, phospholipase Cγ2, and NF-κB increased strongly, suggesting that 14-3-3 also regulates B-cell receptor (BCR)-mediated tonic signaling. Furthermore, downregulation of 14-3-3ζ elevated nuclear translocation of Btk. The loss-of-function mutant S51A/T495A showed reduced tyrosine phosphorylation and ubiquitination. Conversely, the gain-of-function mutant S51D/T495D exhibited intense tyrosine phosphorylation, associated with Btk ubiquitination and degradation, likely contributing to the termination of BCR signaling. Collectively, this suggests that Btk could become an important new candidate for the general study of 14-3-3-mediated regulation. LY294002相似文献