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1
Kuspiel, Sven, Dominik Wiemuth, and Stefan Gründer. "The Neuropeptide Nocistatin Is Not a Direct Agonist of Acid-Sensing Ion Channel 1a (ASIC1a)." Biomolecules 11, no. 4 (April 13, 2021): 571. http://dx.doi.org/10.3390/biom11040571.
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Acid-sensing ion channels (ASICs) are ionotropic receptors that are directly activated by protons. Although protons have been shown to act as a neurotransmitter and to activate ASICs during synaptic transmission, it remains a possibility that other ligands directly activate ASICs as well. Neuropeptides are attractive candidates for alternative agonists of ASICs, because related ionotropic receptors are directly activated by neuropeptides and because diverse neuropeptides modulate ASICs. Recently, it has been reported that the neuropeptide nocistatin directly activates ASICs, including ASIC1a. Here we show that nocistatin does not directly activate ASIC1a expressed in Xenopus oocytes or CHO cells. Moreover, we show that nocistatin acidifies the bath solution to an extent that can fully explain the previously reported activation by this highly acidic peptide. In summary, we conclude that nocistatin only indirectly activates ASIC1a via acidification of the bath solution.
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Schonhoff, Christopher M., Se Won Park, Cynthia R. L. Webster, and M. Sawkat Anwer. "p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 11 (June 1, 2016): G999—G1005. http://dx.doi.org/10.1152/ajpgi.00005.2016.
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In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.
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Barger, Philip M., Alyssa C. Browning, Ashley N. Garner, and Daniel P. Kelly. "p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α." Journal of Biological Chemistry 276, no. 48 (September 27, 2001): 44495–501. http://dx.doi.org/10.1074/jbc.m105945200.
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Yeh, Yi-Chun, and Anant B. Parekh. "Distinct Structural Domains of Caveolin-1 Independently Regulate Ca2+Release-Activated Ca2+Channels and Ca2+Microdomain-Dependent Gene Expression." Molecular and Cellular Biology 35, no. 8 (February 2, 2015): 1341–49. http://dx.doi.org/10.1128/mcb.01068-14.
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In eukaryotic cells, calcium entry across the cell surface activates nuclear gene expression, a process critically important for cell growth and differentiation, learning, and memory and immune cell functions. In immune cells, calcium entry occurs through store-operated Ca2+release-activated Ca2+(CRAC) channels, comprised of STIM1 and Orai1 proteins. Local calcium entry through CRAC channels activates expression of c-fos- and nuclear factor of activated T cells (NFAT)-dependent genes. Although c-fos and NFAT often interact to activate gene expression synergistically, they can be activated independently of one another to regulate distinct genes. This raises the question of how one transcription factor can be activated and not the other when both are stimulated by the same trigger. Here, we show that the lipid raft scaffolding protein caveolin-1 interacts with the STIM1-Orai1 complex to increase channel activity. Phosphorylation of tyrosine 14 on caveolin-1 regulates CRAC channel-evoked c-fos activation without impacting the NFAT pathway or Orai1 activity. Our results reveal that structurally distinct domains of caveolin-1 selectively regulate the ability of local calcium to activate distinct transcription factors. More generally, our findings reveal that modular regulation by a scaffolding protein provides a simple, yet effective, mechanism to tunnel a local signal down a specific pathway.
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Shiozaki, Kazuhiro, Mitsue Shiozaki, and Paul Russell. "Heat Stress Activates Fission Yeast Spc1/StyI MAPK by a MEKK-Independent Mechanism." Molecular Biology of the Cell 9, no. 6 (June 1998): 1339–49. http://dx.doi.org/10.1091/mbc.9.6.1339.
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Fission yeast Spc1/StyI MAPK is activated by many environmental insults including high osmolarity, oxidative stress, and heat shock. Spc1/StyI is activated by Wis1, a MAPK kinase (MEK), which is itself activated by Wik1/Wak1/Wis4, a MEK kinase (MEKK). Spc1/StyI is inactivated by the tyrosine phosphatases Pyp1 and Pyp2. Inhibition of Pyp1 was recently reported to play a crucial role in the oxidative stress and heat shock responses. These conclusions were based on three findings: 1) osmotic, oxidative, and heat stresses activate Spc1/StyI in wis4 cells; 2) oxidative stress and heat shock activate Spc1/StyI in cells that express Wis1AA, in which MEKK consensus phosphorylation sites were replaced with alanine; and 3) Spc1/StyI is maximally activated in Δpyp1 cells. Contrary to these findings, we report: 1) Spc1/StyI activation by osmotic stress is greatly reduced in wis4 cells; 2)wis1-AA and Δwis1 cells have identical phenotypes; and 3) all forms of stress activate Spc1/StyI inΔpyp1 cells. We also report that heat shock, but not osmotic or oxidative stress, activate Spc1 in wis1-DDcells, which express Wis1 protein that has the MEKK consensus phosphorylation sites replaced with aspartic acid. Thus osmotic and oxidative stress activate Spc1/StyI by a MEKK-dependent process, whereas heat shock activates Spc1/StyI by a novel mechanism that does not require MEKK activation or Pyp1 inhibition.
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DeFea, K. A., J. Zalevsky, M. S. Thoma, O. Déry, R. D. Mullins, and N. W. Bunnett. "β-Arrestin–Dependent Endocytosis of Proteinase-Activated Receptor 2 Is Required for Intracellular Targeting of Activated Erk1/2." Journal of Cell Biology 148, no. 6 (March 20, 2000): 1267–82. http://dx.doi.org/10.1083/jcb.148.6.1267.
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Recently, a requirement for β-arrestin–mediated endocytosis in the activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) by several G protein–coupled receptors (GPCRs) has been proposed. However, the importance of this requirement for function of ERK1/2 is unknown. We report that agonists of Gαq-coupled proteinase–activated receptor 2 (PAR2) stimulate formation of a multiprotein signaling complex, as detected by gel filtration, immunoprecipitation and immunofluorescence. The complex, which contains internalized receptor, β-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. However, ERK1/2 activity is retained in the cytosol and neither translocates to the nucleus nor causes proliferation. In contrast, a mutant PAR2 (PAR2δST363/6A), which is unable to interact with β-arrestin and, thus, does not desensitize or internalize, activates ERK1/2 by a distinct pathway, and fails to promote both complex formation and cytosolic retention of the activated ERK1/2. Whereas wild-type PAR2 activates ERK1/2 by a PKC-dependent and probably a ras-independent pathway, PAR2(δST363/6A) appears to activate ERK1/2 by a ras-dependent pathway, resulting in increased cell proliferation. Thus, formation of a signaling complex comprising PAR2, β-arrestin, raf-1, and activated ERK1/2 might ensure appropriate subcellular localization of PAR2-mediated ERK activity, and thereby determine the mitogenic potential of receptor agonists.
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Rao, LV, SI Rapaport, and SP Bajaj. "Activation of human factor VII in the initiation of tissue factor- dependent coagulation." Blood 68, no. 3 (September 1, 1986): 685–91. http://dx.doi.org/10.1182/blood.v68.3.685.685.
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Abstract We have used activation peptide release assays to compare factor VII and activated factor VII (VIIa) activation of factor X, normal factor IX (IXN), and a variant factor IX (IXBmLE), which, after activation, is unable to back-activate factor VII. In purified systems, factor VII and VIIa each rapidly activated factor X, but after a one minute lag for factor VII. VIIa also readily activated both IXN and IXBmLE. Factor VII initially failed to activate substantial amounts of either IXN or IXBmLE; on further incubation factor VII activated IXN but not IXBmLE. Activation of IXN began when approximately 10% of factor VII had been converted to VIIa, as measured by 125I-factor VII radioactivity profiles. Adding factor VII to VIIa slowed its activation of IXBmLE. However, in the presence of factor X, factor VII alone rapidly activated IXBmLE. Unlike purified systems, 1 nmol/L VIIa added to factor VII-deficient plasma failed to activate factor IX. Increasing factor VII to 10 nmol/L (plasma concentration) either as native VII or VIIa yielded similar activation curves for factor IX and similar activation curves for factor X. Adding 5% VIIa to factor X-deficient plasma and to factor XII-deficient plasma substantially shortened the dilute tissue factor clotting time of only the former. These data support the hypothesis that factor VII/tissue factor complex initiates tissue factor-dependent clotting through a minimal generation of Xa. This Xa then rapidly back-activates a small amount of factor VII, following which the rates of activation of both factors IX and X increase dramatically.
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Rao, LV, SI Rapaport, and SP Bajaj. "Activation of human factor VII in the initiation of tissue factor- dependent coagulation." Blood 68, no. 3 (September 1, 1986): 685–91. http://dx.doi.org/10.1182/blood.v68.3.685.bloodjournal683685.
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We have used activation peptide release assays to compare factor VII and activated factor VII (VIIa) activation of factor X, normal factor IX (IXN), and a variant factor IX (IXBmLE), which, after activation, is unable to back-activate factor VII. In purified systems, factor VII and VIIa each rapidly activated factor X, but after a one minute lag for factor VII. VIIa also readily activated both IXN and IXBmLE. Factor VII initially failed to activate substantial amounts of either IXN or IXBmLE; on further incubation factor VII activated IXN but not IXBmLE. Activation of IXN began when approximately 10% of factor VII had been converted to VIIa, as measured by 125I-factor VII radioactivity profiles. Adding factor VII to VIIa slowed its activation of IXBmLE. However, in the presence of factor X, factor VII alone rapidly activated IXBmLE. Unlike purified systems, 1 nmol/L VIIa added to factor VII-deficient plasma failed to activate factor IX. Increasing factor VII to 10 nmol/L (plasma concentration) either as native VII or VIIa yielded similar activation curves for factor IX and similar activation curves for factor X. Adding 5% VIIa to factor X-deficient plasma and to factor XII-deficient plasma substantially shortened the dilute tissue factor clotting time of only the former. These data support the hypothesis that factor VII/tissue factor complex initiates tissue factor-dependent clotting through a minimal generation of Xa. This Xa then rapidly back-activates a small amount of factor VII, following which the rates of activation of both factors IX and X increase dramatically.
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Quayle, J. M., M. R. Turner, H. E. Burrell, and T. Kamishima. "Effects of hypoxia, anoxia, and metabolic inhibitors on KATP channels in rat femoral artery myocytes." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 1 (July 2006): H71—H80. http://dx.doi.org/10.1152/ajpheart.01107.2005.
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Vascular ATP-sensitive potassium (KATP) channels have an important role in hypoxic vasodilation. Because KATP channel activity depends on intracellular nucleotide concentration, one hypothesis is that hypoxia activates channels by reducing cellular ATP production. However, this has not been rigorously tested. In this study we measured KATP current in response to hypoxia and modulators of cellular metabolism in single smooth muscle cells from the rat femoral artery by using the whole cell patch-clamp technique. KATP current was not activated by exposure of cells to hypoxic solutions (Po2 ∼35 mmHg). In contrast, voltage-dependent calcium current and the depolarization-induced rise in intracellular calcium concentration ([Ca2+]i) was inhibited by hypoxia. Blocking mitochondrial ATP production by using the ATP synthase inhibitor oligomycin B (3 μM) did not activate current. Blocking glycolytic ATP production by using 2-deoxy-d-glucose (5 mM) also did not activate current. The protonophore carbonyl cyanide m-chlorophenylhydrazone (1 μM) depolarized the mitochondrial membrane potential and activated KATP current. This activation was reversed by oligomycin B, suggesting it occurred as a consequence of mitochondrial ATP consumption by ATP synthase working in reverse mode. Finally, anoxia induced by dithionite (0.5 mM) also depolarized the mitochondrial membrane potential and activated KATP current. Our data show that: 1) anoxia but not hypoxia activates KATP current in femoral artery myocytes; and 2) inhibition of cellular energy production is insufficient to activate KATP current and that energy consumption is required for current activation. These results suggest that vascular KATP channels are not activated during hypoxia via changes in cell metabolism. Furthermore, part of the relaxant effect of hypoxia on rat femoral artery may be mediated by changes in [Ca2+]i through modulation of calcium channel activity.
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Izumi, T., and J. L. Maller. "Phosphorylation and activation of the Xenopus Cdc25 phosphatase in the absence of Cdc2 and Cdk2 kinase activity." Molecular Biology of the Cell 6, no. 2 (February 1995): 215–26. http://dx.doi.org/10.1091/mbc.6.2.215.
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The M-phase inducer, Cdc25C, is a dual-specificity phosphatase that directly phosphorylates and activates the cyclin B/Cdc2 kinase complex, leading to initiation of mitosis. Cdc25 itself is activated at the G2/M transition by phosphorylation on serine and threonine residues. Previously, it was demonstrated that Cdc2 kinase is capable of phosphorylating and activating Cdc25, suggesting the existence of a positive feedback loop. In the present study, kinases other than Cdc2 that can phosphorylate and activate Cdc25 were investigated. Cdc25 was found to be phosphorylated and activated by cyclin A/Cdk2 and cyclin E/Cdk2 in vitro. However, in interphase Xenopus egg extracts with no detectable Cdc2 and Cdk2, treatment with the phosphatase inhibitor microcystin activated a distinct kinase that could phosphorylate and activate Cdc25. Microcystin also induced other mitotic phenomena such as chromosome condensation and nuclear envelope breakdown in extracts containing less than 5% of the mitotic level of Cdc2 kinase activity. These findings implicate a kinase other than Cdc2 and Cdk2 that may initially activate Cdc25 in vivo and suggest that this kinase may also phosphorylate M-phase substrates even in the absence of Cdc2 kinase.
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Posada, J., N. Yew, N. G. Ahn, G. F. Vande Woude, and J. A. Cooper. "Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro." Molecular and Cellular Biology 13, no. 4 (April 1993): 2546–53. http://dx.doi.org/10.1128/mcb.13.4.2546-2553.1993.
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Several protein kinases, including Mos, maturation-promoting factor (MPF), mitogen-activated protein (MAP) kinase, and MAP kinase kinase (MAPKK), are activated when Xenopus oocytes enter meiosis. De novo synthesis of the Mos protein is required for progesterone-induced meiotic maturation. Recently, bacterially synthesized maltose-binding protein (MBP)-Mos fusion protein was shown to be sufficient to initiate meiosis I and MPF activation in fully grown oocytes in the absence of protein synthesis. Here we show that MAP kinase is rapidly phosphorylated and activated following injection of wild-type, but not kinase-inactive mutant, MBP-Mos into fully grown oocytes. MAP kinase activation by MBP-Mos occurs within 20 min, much more rapidly than in progesterone-treated oocytes. The MBP-Mos fusion protein also activates MPF, but MPF activation does not occur until approximately 2 h after injection. Extracts from oocytes injected with wild-type but not kinase-inactive MBP-Mos contain an activity that can phosphorylate MAP kinase, suggesting that Mos directly or indirectly activates a MAPKK. Furthermore, activated MBP-Mos fusion protein is able to phosphorylate and activate a purified, phosphatase-treated, rabbit muscle MAPKK in vitro. Thus, in oocytes, Mos is an upstream activator of MAP kinase which may function through direct phosphorylation of MAPKK.
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Posada, J., N. Yew, N. G. Ahn, G. F. Vande Woude, and J. A. Cooper. "Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro." Molecular and Cellular Biology 13, no. 4 (April 1993): 2546–53. http://dx.doi.org/10.1128/mcb.13.4.2546.
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Several protein kinases, including Mos, maturation-promoting factor (MPF), mitogen-activated protein (MAP) kinase, and MAP kinase kinase (MAPKK), are activated when Xenopus oocytes enter meiosis. De novo synthesis of the Mos protein is required for progesterone-induced meiotic maturation. Recently, bacterially synthesized maltose-binding protein (MBP)-Mos fusion protein was shown to be sufficient to initiate meiosis I and MPF activation in fully grown oocytes in the absence of protein synthesis. Here we show that MAP kinase is rapidly phosphorylated and activated following injection of wild-type, but not kinase-inactive mutant, MBP-Mos into fully grown oocytes. MAP kinase activation by MBP-Mos occurs within 20 min, much more rapidly than in progesterone-treated oocytes. The MBP-Mos fusion protein also activates MPF, but MPF activation does not occur until approximately 2 h after injection. Extracts from oocytes injected with wild-type but not kinase-inactive MBP-Mos contain an activity that can phosphorylate MAP kinase, suggesting that Mos directly or indirectly activates a MAPKK. Furthermore, activated MBP-Mos fusion protein is able to phosphorylate and activate a purified, phosphatase-treated, rabbit muscle MAPKK in vitro. Thus, in oocytes, Mos is an upstream activator of MAP kinase which may function through direct phosphorylation of MAPKK.
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Xing, Jun, Jon M. Kornhauser, Zhengui Xia, Elizabeth A. Thiele, and Michael E. Greenberg. "Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation." Molecular and Cellular Biology 18, no. 4 (April 1, 1998): 1946–55. http://dx.doi.org/10.1128/mcb.18.4.1946.
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ABSTRACT The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.
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Westwick, John K., Alicja E. Bielawska, Ghassan Dbaibo, Yusuf A. Hannun, and David A. Brenner. "Ceramide Activates the Stress-activated Protein Kinases." Journal of Biological Chemistry 270, no. 39 (September 29, 1995): 22689–92. http://dx.doi.org/10.1074/jbc.270.39.22689.
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Cooper, Dawn M., Dmitri V. Pechkovsky, Tillie L. Hackett, Darryl A. Knight, and David J. Granville. "Granzyme K Activates Protease-Activated Receptor-1." PLoS ONE 6, no. 6 (June 30, 2011): e21484. http://dx.doi.org/10.1371/journal.pone.0021484.
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Shuttleworth, Trevor J., Jill L. Thompson, and Olivier Mignen. "ARC Channels: A Novel Pathway for Receptor-Activated Calcium Entry." Physiology 19, no. 6 (December 2004): 355–61. http://dx.doi.org/10.1152/physiol.00018.2004.
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In many nonexcitable cells, stimulation with low agonist concentrations specifically activates Ca2+ entry via arachidonic acid-regulated, highly Ca2+-selective ARC channels. Only at high agonist concentrations are the more widely studied store-operated channels activated, producing sustained elevated cytosolic Ca2+ concentration signals. These signals activate calcineurin, which in turn inhibits the ARC channels, resulting in a “reciprocal regulation” of these two distinct Ca2+-entry pathways that may have important functional implications for the cell.
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Xiao, B. G., X. F. Bai, G. X. Zhang, and H. Link. "Activated T cells activate microglia in vitro." Journal of Neuroimmunology 63, no. 1 (December 1995): 94. http://dx.doi.org/10.1016/0165-5728(96)80951-9.
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DiPolo, R., and L. Beaugé. "Characterization of the reverse Na/Ca exchange in squid axons and its modulation by Cai and ATP. Cai-dependent Nai/Cao and Nai/Nao exchange modes." Journal of General Physiology 90, no. 4 (October 1, 1987): 505–25. http://dx.doi.org/10.1085/jgp.90.4.505.
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We have used dialyzed squid axons to characterize the ouabain- and bumetanide-insensitive Na efflux components and their relation to the operation of the Na/Ca exchange mechanism. In axons dialyzed with solutions containing nearly physiological concentrations of K, Na, and Mg, three components of the Na efflux can be distinguished: Cai-activated, Cao-dependent Na efflux ("reverse" Na/Ca exchange); Cai-activated, Nao-dependent Na efflux; and Cai-independent, ATP-activated, Nao-dependent Na efflux. We have studied the effects of internal alkalinization, Mgi, Cao, and the ATP analogue [gamma-thio]ATP (ATP gamma S) on the different components of the Na efflux. The results show the following: (a) internal alkalinization activates both Cao- and Nao-dependent Na efflux components provided that Cai is present; (b) Mgi inhibits both the Cai-activated, Cao- and Nao-dependent Na efflux components; (c) Cao inhibits the Nao-dependent component by competition for a common site; (d) ATP gamma S activates both Nao- and Cao-dependent Na efflux components only in the presence of Cai; and (e) ATP activates the Nai/Nao and Nai/Cao exchanges, causing a 10-fold increase in the affinity of the reverse Na/Ca exchange toward Cai. In the absence of Cai, ATP stimulates an Nao-dependent Na efflux that is not affected either by internal alkalinization or high Cao. The ATP analogue does not activate the Cai-independent Na/Na exchange system. These experiments demonstrate that the Cai-activated Na/Na exchange is a mode of operation of the Na/Ca exchange mechanism that substantially contributes to Na movement during the activation of the Na/Ca antiporter. The experimental evidence obtained on the Cai-independent Na/Na exchange component shows that this system is not part of the Na/Ca exchange.
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Aprilia, Yeni, Arnelli Arnelli, and Yayuk Astuti. "Modification of Activated Carbon from Rice Husk using Hexadecyltrimethylammonium Bromide (HDTMA-Br) Surfactant and ZnCl2 activator and Microwaves for Nitrate Ion Adsorption." Jurnal Kimia Sains dan Aplikasi 23, no. 11 (November 6, 2020): 377–82. http://dx.doi.org/10.14710/jksa.23.11.377-382.
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Surfactant Modified Activated Carbon (SMAC) is a surfactant-modified activated carbon product. The surfactant used in this study was the cationic surfactant Hexadecyltrimethylammonium Bromide (HDTMA-Br). These surfactants can change the activated carbon's surface to be positively charged due to the presence of the surfactant hydrophilic groups. This SMAC is more selective in absorbing anions, which in this study is for the adsorption of nitrate anions. This research aims to prepare a new material that is superior to activated carbon in absorbing nitrate anions. This research was conducted in several stages. In the first stage, rice husk was carbonized through pyrolysis at 300°C for 10 minutes. In the second stage, carbon was activated using 30% ZnCl2 and microwaves for 5 minutes and 400 W. The third stage was modifying activated carbon by contacting or adsorbing HDTMA-Br on activated carbon. The concentration of HDTMA-Br varied at 200-400 ppm and the adsorption time was 3-7 hours. The success of the modification was measured by the efficiency of HDTMA-Br in modifying activated carbon. This is supported by the results of the characterization of FTIR, GSA, SEM, and thermodynamic parameters. The resulting SMAC was applied for the adsorption of nitrate anions, and the results were compared to carbon and activated carbon. The results indicate that the best SMAC is formed at an optimum concentration of 300 ppm, within 4 hours, with an adsorption efficiency of 97.345%. The characterization results also show that SMAC has been formed, as evidenced by the presence of a peak at a wavenumber of about 1500 cm-1, a C-N group derived from N(CH3)3 in the HDTMA-Br surfactant structure. The SMAC spectra also appeared weak peaks at the wave number 2918 cm-1, which indicated the CH2-R group stretching from the HDTMA-Br surfactant. SEM image shows that HDTMA-Br has covered the pores of activated carbon. Meanwhile, the SMAC surface area is lower than that of activated carbon. Thermodynamic parameters indicate that HDTMA-Br interacts physically with activated carbon. The adsorption capacity of nitrate anion by SMAC is 3,638 mg/g, higher than carbon and activated carbon.
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Rachmilewitz, Jacob, and Mark L. Tykocinski. "Differential Effects of Chondroitin Sulfates A and B on Monocyte and B-Cell Activation: Evidence for B-Cell Activation Via a CD44-Dependent Pathway." Blood 92, no. 1 (July 1, 1998): 223–29. http://dx.doi.org/10.1182/blood.v92.1.223.413k15_223_229.
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At inflammatory sites, proteoglycans are both secreted by activated mononuclear leukocytes and released as a consequence of extracellular matrix degradation. Chondroitin 4-sulfate proteoglycans constitute the predominant ones produced by activated human monocytes/macrophages. In this study, we show that two chondroitin 4-sulfate forms, CSA and CSB, can activate distinct peripheral blood mononuclear cell types. Whereas CSA activates monocytes (to secrete monokines), CSB activates B-cells (to proliferate). In contrast, the chondroitin 6-sulfate CSC and heparin do not exert these functional effects. We further show that CD44 monoclonal antibodies block CSB-induced B-cell proliferation. These findings point to glycosaminoglycans, and specifically chondroitin 4-sulfates, as a novel class of immunological mediators at inflammatory sites. Furthermore, the data link CD44 to B-cell activation, paralleling the established roles of CD44 in T-cell and monocyte activation.
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Chadee, Deborah N. "Involvement of mixed lineage kinase 3 in cancer." Canadian Journal of Physiology and Pharmacology 91, no. 4 (April 2013): 268–74. http://dx.doi.org/10.1139/cjpp-2012-0258.
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Mitogen-activated protein kinase (MAPK) signaling pathways are composed of a phosphorelay signaling module where an activated MAP kinase kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MAP2K) that in turn phosphorylates and activates a MAPK. The biological outcome of MAPK signaling is the regulation of cellular responses such as proliferation, differentiation, migration, and apoptosis. The MAP3K mixed lineage kinase 3 (MLK3) phosphorylates MAP2Ks to activate multiple MAPK signaling pathways, and MLK3 also has functions in cell signaling that are independent of its kinase activity. The recent elucidation of essential functions for MLK3 in tumour cell proliferation, migration, and invasion has drawn attention to the MLKs as potential therapeutic targets for cancer treatments. The mounting evidence that suggests a role for MLK3 in tumourigenesis and establishment of the malignant phenotype is the focus of this review.
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Yan, Dandan, Rue Li, and Le Gao. "Research progress of limulus coagulation mechanism and limulus reagents." BIO Web of Conferences 111 (2024): 01016. http://dx.doi.org/10.1051/bioconf/202411101016.
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The coagulation system of Limulus is mainly composed of coagulation proteins such as factor G, factor C, factor B, and prothrombin. The traditional horseshoe crab reagent for endotoxin detection is not specific, and its colorimetric reaction is activated through two pathways: one is activated by endotoxin to activate factor C, and the other is activated by (1,3)- β-D-glucan activates factor G. The horseshoe crab reagent is composed of a series of serine proteases and is a biological reagent made by treating horseshoe crab blood cell lysate. The detection principle is that the Limulus amebocyte lysate clotting factor protein is activated by endotoxin or fungal glucan to generate a series of cascade reactions to form insoluble gel substances, and then it is used to detect bacterial endotoxin or fungal glucan contaminated in biological products through the chromogenic reaction of the chromogenic matrix. Mainly used in multiple fields such as drug inspection, food, medical equipment, clinical medical research, etc. This article mainly summarizes and summarizes the coagulation mechanism of horseshoe crab and the current development status of horseshoe crab reagents.
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Browe, David M., and Clive M. Baumgarten. "Stretch of β1 Integrin Activates an Outwardly Rectifying Chloride Current via FAK and Src in Rabbit Ventricular Myocytes." Journal of General Physiology 122, no. 6 (November 10, 2003): 689–702. http://dx.doi.org/10.1085/jgp.200308899.
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Osmotic swelling of cardiac myocytes and other types of cells activates an outwardly rectifying, tamoxifen-sensitive Cl− current, ICl,swell, but it is unclear whether Cl− currents also are activated by direct mechanical stretch. We tested whether specific stretch of β1-integrin activates a Cl− current in rabbit left ventricular myocytes. Paramagnetic beads (4.5-μm diameter) coated with mAb to β1-integrin were applied to the surface of myocytes and pulled upward with an electromagnet while recording whole-cell current. In solutions designed to isolate anion currents, β1-integrin stretch elicited an outwardly rectifying Cl− current with biophysical and pharmacological properties similar to those of ICl,swell. Stretch-activated Cl− current activated slowly (t1/2 = 3.5 ± 0.1 min), partially inactivated at positive voltages, reversed near ECl, and was blocked by 10 μM tamoxifen. When stretch was terminated, 64 ± 8% of the stretch-induced current reversed within 10 min. Mechanotransduction involved protein tyrosine kinase. Genistein (100 μM), a protein tyrosine kinase inhibitor previously shown to suppress ICl,swell in myocytes, inhibited stretch-activated Cl− current by 62 ± 6% during continued stretch. Because focal adhesion kinase and Src are known to be activated by cell swelling, mechanical stretch, and clustering of integrins, we tested whether these tyrosine kinases mediated the response to β1-integrin stretch. PP2 (10 μM), a selective blocker of focal adhesion kinase and Src, fully inhibited the stretch-activated Cl− current as well as part of the background Cl− current, whereas its inactive analogue PP3 (10 μM) had no significant effect. In addition to activating Cl− current, stretch of β1-integrin also appeared to activate a nonselective cation current and to suppress IK1. Integrins are the primary mechanical link between the extracellular matrix and cytoskeleton. The present results suggest that integrin stretch may contribute to mechano-electric feedback in heart, modulate electrical activity, and influence the propensity for arrhythmogenesis.
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Liu, XueQiao, and Jeffrey I. Cohen. "Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase." Journal of Virology 90, no. 2 (November 11, 2015): 1129–38. http://dx.doi.org/10.1128/jvi.01410-15.
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ABSTRACTEpstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus associated with both B cell and epithelial cell malignancies. EBV infection of B cells triggers activation of several signaling pathways that are critical for cell survival, virus latency, and growth transformation. To identify EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 and NF-κB promoter activity in AP-1– and NF-κB–luciferase reporter assays. We found that EBV BGLF2 activated AP-1 but not NF-κB reporter activity. Expression of EBV BGLF2 in cells activated p38 and c-Jun N-terminal kinase (JNK), both of which are important for mitogen-activated protein kinase (MAPK) signaling. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of BGLF2 to activate JNK and p38. Expression of BGLF2 enhanced BZLF1 expression in latently EBV-infected lymphoblastoid cell lines, and knockdown of BGLF2 reduced EBV reactivation induced by IgG cross-linking. Expression of BGLF2 induced BZLF1 expression and virus production in EBV-infected gastric carcinoma cells. BGLF2 enhanced BZLF1 expression and EBV production by activating p38; chemical inhibition of p38 and MAPK/ERK kinases 1 and 2 (MEK1/2) reduced expression of BZLF1 and virus production induced by BGLF2. In summary, the EBV tegument protein BGLF2, which is delivered to the cell at the onset of virus infection, activates the AP-1 pathway and enhances EBV reactivation and virus production.IMPORTANCEEpstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency.
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Kida, Yutaka, Hiroyoshi Inoue, Takashi Shimizu, and Koichi Kuwano. "Serratia marcescens Serralysin Induces Inflammatory Responses through Protease-Activated Receptor 2." Infection and Immunity 75, no. 1 (October 16, 2006): 164–74. http://dx.doi.org/10.1128/iai.01239-06.
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ABSTRACT The Serratia marcescens-derived protease serralysin is considered to play an important role in the pathogenesis of infection. Protease-activated receptor 2 (PAR-2) is activated by trypsin and also several other trypsin-like serine proteases, leading to the modulation of inflammatory and immune responses. However, little is known about the activation of PAR-2 by bacterial proteases and its roles in bacterial infection. In this study, we investigated whether S. marcescens serralysin activates host inflammatory responses through PAR-2. Our results demonstrated that serralysin induces interleukin-6 (IL-6) and IL-8 mRNA expression in a human lung squamous cell carcinoma, EBC-l cells. In addition, serralysin activated activator protein 1 (AP-1)-, CCAAT/enhancer-binding protein (C/EBP)-, and nuclear factor-κB (NF-κB)-driven promoters in EBC-1 cells. An electrophoretic mobility shift assay showed that serralysin activates the binding of AP-1, C/EBPβ, and NF-κB in the cells. Inactivation of serralysin resulted in the failure of transactivation of AP-1-, C/EBP-, and NF-κB-driven promoters in the cells. Furthermore, serralysin activated AP-1-, C/EBP-, and NF-κB-driven promoters via PAR-2 in HeLa cells. PAR-2 antagonist peptides decreased serralysin-induced transactivation of AP-1-, C/EBP-, and NF-κB-driven promoters in EBC-1 cells. Considered together, these results suggest that serralysin requires PAR-2 to activate the critical transcription factors AP-1, C/EBPβ, and NF-κB for host inflammatory responses.
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Brezina, V., C. G. Evans, and K. R. Weiss. "Characterization of the membrane ion currents of a model molluscan muscle, the accessory radula closer muscle of Aplysia californica. II. Depolarization-activated K currents." Journal of Neurophysiology 71, no. 6 (June 1, 1994): 2113–25. http://dx.doi.org/10.1152/jn.1994.71.6.2113.
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1. The accessory radula closer (ARC) muscle of Aplysia californica and its innervation is a model preparation for the study of the neural and cellular mechanisms of behavioral plasticity. Much of the plasticity is mediated by release of neurotransmitters and peptide cotransmitters that modulate contractions of the muscle. Preliminary to investigating the cellular mechanisms of action of these modulators, we have characterized the major membrane ion currents present in the unmodulated ARC muscle and their likely roles in normal contraction. We have studied single dissociated but functionally intact ARC muscle fibers under voltage clamp. This is the second of three papers describing this work. In the preceding paper we described the electrophysiological properties of the fibers at hyperpolarized voltages, and characterized the two major hyperpolarized-activated currents present, a classical inwardly rectifying K current and a Cl current induced by elevated intracellular Cl-. 2. In this paper we dissect the large outward current that becomes activated when the fibers are depolarized above -50 or -40 mV. We find that this current consists of two major depolarization-activated K currents, a fast transient “A”-type current and a slower maintained delayed rectifier, with perhaps a small component of Ca(2+)-activated K current. 3. The A current begins to activate with voltage steps above -50 or -40 mV. It activates in milliseconds, then inactivates virtually completely within 100–200 ms. It is fully available for activation below -80 mV, and almost completely inactivated above -40 mV. It is Ca2+ independent, half-maximally blocked by approximately 3 mM 4-aminopyridine (4-AP) but only 460 mM tetraethylammonium (TEA). 4. The delayed rectifier both activates and inactivates more slowly and more positive than the A current. Thus it begins to activate only above -30 or -20 mV; it activates in tens of milliseconds, then inactivates incompletely over several seconds; it is fully available below -70 mV and inactivated above 0 mV. It is Ca2+ independent, half-maximally blocked by 10 mM TEA and 3–10 mM 4-AP. 5. In the following paper we describe a depolarization-activated Ca current that underlies the K currents and most likely provides Ca2+ necessary for contraction of the muscle. By activating simultaneously with the Ca current, the K currents serve to prevent spikes, so that the depolarization is confined to a range where small voltage changes provide fine control over a wide range of contraction strengths.
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Gailani, David, David Ho, Mao-Fu Sun, Qiufang Cheng, and Peter N. Walsh. "Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential." Blood 97, no. 10 (May 15, 2001): 3117–22. http://dx.doi.org/10.1182/blood.v97.10.3117.
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Abstract Human coagulation factor XI (FXI) is a plasma serine protease composed of 2 identical 80-kd polypeptides connected by a disulfide bond. This dimeric structure is unique among blood coagulation enzymes. The hypothesis was tested that dimeric conformation is required for normal FXI function by generating a monomeric version of FXI (FXI/PKA4) and comparing it to wild-type FXI in assays requiring factor IX activation by activated FXI (FXIa). FXI/PKA4 was made by replacing the FXI A4 domain with the A4 domain from prekallikrein (PK). A dimeric version of FXI/PKA4 (FXI/PKA4-Gly326) was prepared as a control. Activated FXI/PKA4 and FXI/PKA4-Gly326 activate factor IX with kinetic parameters similar to those of FXIa. In kaolin-triggered plasma clotting assays containing purified phospholipid, FXI/PKA4 and FXI/PKA4-Gly326 have coagulant activity similar to FXI. The surface of activated platelets is likely to be a physiologic site for reactions involving FXI/FXIa. In competition binding assays FXI/PKA4, FXI/PKA4-Gly326, and FXI have similar affinities for activated platelets (Ki = 12-16 nM). In clotting assays in which phospholipid is replaced by activated platelets, the dimeric proteins FXI and FXI/PKA4-Gly326 promote coagulation similarly; however, monomeric FXI/PKA4 has greatly reduced activity. Western immunoblot analysis confirmed that activated monomeric FXI/PKA4 activates factor IX poorly in the presence of activated platelets. These findings demonstrate the importance of the dimeric state to FXI activity and suggest a novel model for factor IX activation in which FXIa binds to activated platelets by one chain of the dimer, while binding to factor IX through the other.
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Wong, Rosanna Yin-mei, and Ying-yi Hong. "Dynamic Influences of Culture on Cooperation in the Prisoner's Dilemma." Psychological Science 16, no. 6 (June 2005): 429–34. http://dx.doi.org/10.1111/j.0956-7976.2005.01552.x.
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This study tested whether priming of cultural symbols activates cultural behavioral scripts and thus the corresponding behaviors, and also whether the behaviors activated are context-specific. Specifically, to activate the cultural knowledge of Chinese-American bicultural participants, we primed them with Chinese cultural icons or American cultural icons. In the control condition, we showed them geometric figures. Then, the participants played the Prisoner's Dilemma game with friends or strangers (the context manipulation). As expected, participants showed more cooperation toward friends when Chinese cultural knowledge was activated than when American cultural knowledge was activated. By contrast, participants showed a similarly low level of cooperation toward strangers after both Chinese and American culture priming. These findings not only support previous evidence on culture priming of social judgment and self-construals, but also (a) provide the first evidence for the effects of culture priming on behaviors and (b) demonstrate the boundary condition of culture priming.
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Morioka, Sho, Peter Broglie, Emily Omori, Yuka Ikeda, Giichi Takaesu, Kunihiro Matsumoto, and Jun Ninomiya-Tsuji. "TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation." Journal of Cell Biology 204, no. 4 (February 17, 2014): 607–23. http://dx.doi.org/10.1083/jcb.201305070.
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TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8–mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)–dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.
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Beklen, A., G. Tüter, T. Sorsa, R. Hanemaaijer, I. Virtanen, T. Tervahartiala, and Y. T. Konttinen. "Gingival Tissue and Crevicular Fluid Co-operation in Adult Periodontitis." Journal of Dental Research 85, no. 1 (January 2006): 59–63. http://dx.doi.org/10.1177/154405910608500110.
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Activated matrix metalloproteinase-3 (MMP-3) can contribute to periodontal ligament destruction in adult periodontitis. Since MMP-3 has been reported to activate proMMP-8 and -9, it was speculated that gingival tissue fibroblast-derived MMP-3 might, in periodontitis, be responsible for activation of gingival crevicular fluid (GCF) neutrophil-derived proMMP-8 and -9. Immunohistochemistry disclosed MMP-3 in gingival fibroblasts in periodontitis. Cultured gingival fibroblasts released only pro-MMP-3 when stimulated with tumor necrosis factor-α. However, Western blot revealed partially activated MMP-3, MMP-8, and MMP-9 in periodontitis GCF. Active MMP-8 (p < 0.05) and MMP-9 (p < 0.05) correlated with the presence of active MMP-3. It seems that resident gingival fibroblasts produce pro-MMP-3 in GCF, where it becomes activated, probably by cathepsin G or elastase released by neutrophils. Active MMP-3 then activates neutrophil-derived pro-MMP-8 and -9. Different tissue compartments/cells exert co-operative actions in mutual local MMP activation cascades.
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KITAMURA, Takanori, Kazuhiro KIMURA, Bae Dong JUNG, Kennedy MAKONDO, Naoki SAKANE, Toshihide YOSHIDA, and Masayuki SAITO. "Proinsulin C-peptide activates cAMP response element-binding proteins through the p38 mitogen-activated protein kinase pathway in mouse lung capillary endothelial cells." Biochemical Journal 366, no. 3 (September 15, 2002): 737–44. http://dx.doi.org/10.1042/bj20020344.
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Proinsulin C-peptide has been reported to have some biological activities and to be possibly involved in the development of diabetic microangiopathy. In the present study, we examined the effects of C-peptide on the mitogen-activated protein kinase pathway in LEII mouse lung capillary endothelial cells. Stimulation of the cells with C-peptide increased both p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-regulated kinase (ERK1/2) activities and activity-related site-specific phosphorylation of the respective kinases in a concentration-dependent manner, but failed to activate c-Jun N-terminal kinase. Stimulation of the cells with C-peptide also induced site-specific phosphorylation of cAMP response element (CRE)-binding protein (CREB)/activating transcription factor 1 (ATF1), and thereby binding of these transcription factors to CRE. Among three CREB kinases tested, phosphorylation of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) was induced after stimulation with C-peptide. The phosphorylation of CREB, ATF1 and MAPKAP-K2 were inhibited by SB203580, a p38MAPK inhibitor, but not by PD98059, an ERK kinase inhibitor. These results indicate that C-peptide activates p38MAPK followed by MAPKAP-K2 to enhance DNA—CREB/ATF1 interactions.
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Grgurevic, Srdana, Srdan Verstovsek, Zhiming Liu, Taghi Manshouri, David Harris, Ping Li, Hagop M. Kantarjian, and Zeev Estrov. "Signal Transducer and Activator of Transcription (STAT)-3 Activates Nuclear Factor (NF)-κB in Primary Myelofibrosis (PMF) Bone Marrow Cells." Blood 118, no. 21 (November 18, 2011): 1742. http://dx.doi.org/10.1182/blood.v118.21.1742.1742.
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Abstract Abstract 1742 Primary myelofibrosis (PMF) is a stem cell–derived hematologic malignancy, characterized by an expansion of one or more myeloid lineage resulting in bone marrow (BM) hypercellularity, magakaryocyte proliferation with atypia, granulocytic proliferation, and reticulin and/or collagen fibrosis. An acquired activating mutation in Janus kinase 2 at codon V617F (JAK2V617F) is detected in BM cells of the majority of patients with PMF. Constitutively activated JAK2 induces phosphorylation and activation of STAT3. Phosphorylated STAT3 forms heterodimers, translocates to the nucleus, binds to DNA, activates STAT3-target genes, and induces production of cytokines that interact with the BM microenvironment. Hematopoietic stroma derived soluble factors provide PMF cells with survival advantage (Manshouri et al. Cancer Res 71: 3831, 2011) and, as reported previously, most of these factors activate NF-κB in a variety of cell types. NF-κB plays an important role in the survival and proliferation of normal and neoplastic cells. In several hematologic malignancies, the NF-κB p65/p50 dimers were found to be activated to variable degrees. The activation of NF-κB is mediated by either the canonical pathway or the alternative pathway. The canonical pathway is typically activated by extracellular signals that activate the β subunit of the IκB kinase (IKK) complex (IKKβ) that induces the phosphorylation and degradation of the NF-κB inhibitor IκBα. Following IκBα degradation, NF-κB heterodimers translocate to the nucleus and bind to DNA. We have recently found that in chronic lymphocytic leukemia (CLL) constitutively activated STAT3 induces the production of unphsophorylated (U) STAT3. U-STAT3 binds to the NF-κB dimers p65/p50 in competition with IκB and the U-STAT3/NF-κB complex shuttles to the nucleus where NF-κB binds to DNA and activates NF-κB-regulated genes (Liu et al. Mol Cancer Res 9: 507, 2011). Because in PMF constitutively activated JAK2 induces phosphorylation of STAT3 and this activated form of STAT3 induces the production of U-STAT3, we wondered whether, like in CLL, U-STAT3 activates NF-κB in PMF. To determine whether NF-κB is constitutively activated in PMF we obtained BM low density cells from untreated patients with PMF. First we studied low-density BM cells of 11 patients with PMF using the electrophoretic mobility shift assay (EMSA). Cells of all samples bound to a p65/NF-κB DNA-labeled probe and the addition of an unlabelled (cold) p65/NF-κB probe attenuated or completely eliminated the binding. Typically, NF-κB-DNA binding appears and disappears due to repeated degradation and re-synthesis of IκB and the consequent activation and inactivation of NF-κB, respectively. Because we found that NF-κB is constitutively activated in all PMF BM samples we hypothesized that, like in CLL cells, activation of NF-κB in PMF cells is induced by an IκB-unrelated mechanism as reported by Yang J et al. (Cancer Res 65:939, 2005). By using immunoprecipitation of two different PMF BM samples we determined that STAT3 binds to the RelA/p65 NF-κB protein, and by using EMSA we found that anti-STAT3, similar to anti- NF-κB p65 antibodies, attenuated the binding of PMF BM cell extract to the NF-κB DNA probe. Taken together, our data suggest that U-STAT3 binds the NF-κB dimers p65/p50 and constitutively activates NF-κB in PMF. Disclosures: No relevant conflicts of interest to declare.
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Cacicedo, José M., Marie-Soleil Gauthier, Nathan K. Lebrasseur, Ravi Jasuja, Neil B. Ruderman, and Yasuo Ido. "Acute exercise activates AMPK and eNOS in the mouse aorta." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 4 (October 2011): H1255—H1265. http://dx.doi.org/10.1152/ajpheart.01279.2010.
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Exercise can prevent endothelial cell (EC) dysfunction and atherosclerosis even in the absence of improvements in plasma lipids. However, the mechanisms responsible for these effects are incompletely understood. In this study we examined in mice whether an acute bout of exercise activates enzymes that could prevent EC dysfunction, such as AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). We also examined whether exercise alters known regulators of these enzymes. C57BL/6 mice underwent a single bout of exhaustive treadmill exercise after which their aortas were analyzed for activation of AMPK, AMPK regulatory proteins, eNOS, and various enzymes that, like AMPK, activate eNOS. We found that such exercise acutely activates both AMPK and eNOS in the whole aorta and that the magnitude of these effects correlated with both the distance run and activation of the AMPK regulatory proteins silent information regulator-1 (SIRT1)-LKB1 and CaMKKβ. In contrast, Akt, PKA, PKG, and Src, other kinases known to activate eNOS, were unaffected. Immunohistochemical analysis revealed that AMPK and eNOS were both activated in the ECs of the aorta. This study provides the first evidence that an acute bout of exercise activates AMPK and eNOS in the endothelium of the aorta. The results also suggest that AMPK likely is the principal activator of eNOS in this setting and that its own activation may be mediated by both SIRT1-LKB1 and CaMKKβ.
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Qureshi, Bilal M., Elmar Behrmann, Johannes Schöneberg, Justus Loerke, Jörg Bürger, Thorsten Mielke, Jan Giesebrecht, et al. "It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods." Open Biology 8, no. 8 (August 2018): 180075. http://dx.doi.org/10.1098/rsob.180075.
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Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein α-subunits (Gα*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction–diffusion simulations. Gα* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of Gα* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 Gα* · PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that Gα* · PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of Gα* which binds with lower affinity, forming Gα* · PDE6 · Gα*. Reaction–diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of Gα* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated Gα* fails to activate the effector enzyme.
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Kane, Lesley A., Michael Lazarou, Adam I. Fogel, Yan Li, Koji Yamano, Shireen A. Sarraf, Soojay Banerjee, and Richard J. Youle. "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity." Journal of Cell Biology 205, no. 2 (April 21, 2014): 143–53. http://dx.doi.org/10.1083/jcb.201402104.
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PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin’s ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. These results explain a feed-forward mechanism of PINK1-mediated initiation of Parkin E3 ligase activity.
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Park, Rackhyun, Kang Il Lee, Hyunju Kim, Minsu Jang, Thi Kim Quy Ha, Won Keun Oh, and Junsoo Park. "Reserpine treatment activates AMP activated protein kinase (AMPK)." Natural Product Sciences 23, no. 3 (2017): 157. http://dx.doi.org/10.20307/nps.2017.23.3.157.
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Kawamura, Takeshi, Noriko Okada, and Hidechika Okada. "Elastase from Activated Human Neutrophils Activates Procarboxypeptidase R." Microbiology and Immunology 46, no. 3 (March 2002): 225–30. http://dx.doi.org/10.1111/j.1348-0421.2002.tb02690.x.
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Singh, Sudhir, and Robert G. Bennett. "Relaxin signaling activates peroxisome proliferator-activated receptor gamma." Molecular and Cellular Endocrinology 315, no. 1-2 (February 2010): 239–45. http://dx.doi.org/10.1016/j.mce.2009.08.014.
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Jensen, Liselotte E., and Alexander S. Whitehead. "Pellino2 activates the mitogen activated protein kinase pathway." FEBS Letters 545, no. 2-3 (May 24, 2003): 199–202. http://dx.doi.org/10.1016/s0014-5793(03)00533-7.
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Swoap, Steven J., R. Bridge Hunter, Eric J. Stevenson, Heather Mitchell Felton, Nilesh V. Kansagra, Joshua M. Lang, Karyn A. Esser, and Susan C. Kandarian. "The calcineurin-NFAT pathway and muscle fiber-type gene expression." American Journal of Physiology-Cell Physiology 279, no. 4 (October 1, 2000): C915—C924. http://dx.doi.org/10.1152/ajpcell.2000.279.4.c915.
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To test for a role of the calcineurin-NFAT (nuclear factor of activated T cells) pathway in the regulation of fiber type-specific gene expression, slow and fast muscle-specific promoters were examined in C2C12 myotubes and in slow and fast muscle in the presence of calcineurin or NFAT2 expression plasmids. Overexpression of active calcineurin in myotubes induced both fast and slow muscle-specific promoters but not non-muscle-specific reporters. Overexpression of NFAT2 in myotubes did not activate muscle-specific promoters, although it strongly activated an NFAT reporter. Thus overexpression of active calcineurin activates transcription of muscle-specific promoters in vitro but likely not via the NFAT2 transcription factor. Slow myosin light chain 2 (MLC2) and fast sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) reporter genes injected into rat soleus (slow) and extensor digitorum longus (EDL) (fast) muscles were not activated by coinjection of activated calcineurin or NFAT2 expression plasmids. However, an NFAT reporter was strongly activated by overexpression of NFAT2 in both muscle types. Calcineurin and NFAT protein expression and binding activity to NFAT oligonucleotides were different in slow vs. fast muscle. Taken together, these results indicate that neither calcineurin nor NFAT appear to have dominant roles in the induction and/or maintenance of slow or fast fiber type in adult skeletal muscle. Furthermore, different pathways may be involved in muscle-specific gene expression in vitro vs. in vivo.
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Shen, Jianying, Dang Sun, Jingyu Shao, Yanbo Chen, Keliang Pang, Wei Guo, and Bai Lu. "Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation." Cells 8, no. 8 (August 19, 2019): 932. http://dx.doi.org/10.3390/cells8080932.
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Receptor tyrosine kinases are believed to be activated through ligand-induced dimerization. We now demonstrate that in cultured neurons, a substantial amount of endogenous TrkB, the receptor for brain-derived neurotrophic factor (BDNF), exists as an inactive preformed dimer, and the application of BDNF activates the pre-existing dimer. Deletion of the extracellular juxtamembrane motif (EJM) of TrkB increased the amount of preformed dimer, suggesting an inhibitory role of EJM on dimer formation. Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes. Finally, in cells co-expressing rat and human TrkB, MM12 could only activate TrkB human-human dimer but not TrkB human-rat TrkB dimer, indicating that MM12 binding to two TrkB monomers is required for activation. Our results support a model that TrkB preforms as an inactive dimer and BDNF induces TrkB conformation changes leading to its activation.
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Ramos, Joe W., Paul E. Hughes, Mark W. Renshaw, Martin A. Schwartz, Etienne Formstecher, Hervé Chneiweiss, and Mark H. Ginsberg. "Death Effector Domain Protein PEA-15 Potentiates Ras Activation of Extracellular Signal Receptor-activated Kinase by an Adhesion-independent Mechanism." Molecular Biology of the Cell 11, no. 9 (September 2000): 2863–72. http://dx.doi.org/10.1091/mbc.11.9.2863.
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PEA-15 is a small, death effector-domain (DED)–containing protein that was recently demonstrated to inhibit tumor necrosis factor-α–induced apoptosis and to reverse the inhibition of integrin activation due to H-Ras. This led us to investigate the involvement of PEA-15 in Ras signaling. Surprisingly, PEA-15 activates the extracellular signal receptor-activated kinase (ERK) mitogen-activated protein kinase pathway in a Ras-dependent manner. PEA-15 expression in Chinese hamster ovary cells resulted in an increased mitogen-activated protein kinase kinase and ERK activity. Furthermore, PEA-15 expression leads to an increase in Ras guanosine 5′-triphosphate loading. PEA-15 bypasses the anchorage dependence of ERK activation. Finally, the effects of PEA-15 on integrin signaling are separate from those on ERK activation. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to activate ERK. The ability of PEA-15 to simultaneously inhibit apoptosis and potentiate Ras-to-Erk signaling may be of importance for oncogenic processes.
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Dillon, Tara J., Kendall D. Carey, Scott A. Wetzel, David C. Parker, and Philip J. S. Stork. "Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4." Molecular and Cellular Biology 25, no. 10 (May 15, 2005): 4117–28. http://dx.doi.org/10.1128/mcb.25.10.4117-4128.2005.
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ABSTRACT The mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) is activated following engagement of the T-cell receptor and is required for interleukin 2 (IL-2) production and T-cell proliferation. This activation is enhanced by stimulation of the coreceptor CD28 and inhibited by the coreceptor CTLA-4. We show that the small G protein Rap1 is regulated in the opposite manner; it is inhibited by CD28 and activated by CTLA-4. Together, CD3 and CTLA-4 activate Rap1 in a sustained manner. To delineate T-cell function in the absence of Rap1 activity, we generated transgenic mice expressing Rap1GAP1, a Rap1-specific GTPase-activating protein. Transgenic mice showed lymphadenopathy, and transgenic T cells displayed increased ERK activation, proliferation, and IL-2 production. More significantly, the inhibitory effect of CTLA-4 on T-cell function in Rap1GAP1-transgenic T cells was reduced. We demonstrate that CTLA-4 activates Rap1, and we propose that intracellular signals from CTLA-4 antagonize CD28, at least in part, at the level of Rap1.
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JUPP, Orla J., Peter VANDENABEELE, and David J. MacEWAN. "Distinct regulation of cytosolic phospholipase A2 phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes." Biochemical Journal 374, no. 2 (September 1, 2003): 453–61. http://dx.doi.org/10.1042/bj20030705.
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The hormonally regulated Ca2+-dependent enzyme, cytosolic phospholipase A2 (cPLA2) is activated by a range of inflammatory stimuli. Tumour necrosis factor-α (TNF) is one of the first known stimuli for cPLA2 but it is not known whether both TNF receptor subtypes are involved in activating the lipase. In the present study, we show for the first time that both type I 55 kDa TNFR (TNFR1) and type II 75 kDa TNFR (TNFR2) stimulate cPLA2 enzyme, but with distinct signalling mechanisms. TNFR1 activates mitogen-activated protein kinase (MAPK) and p38MAPK. TNFR1 then phosphorylates and activates cPLA2 in a MAPK-dependent fashion. Furthermore, TNFR1 causes the translocation and caspase-dependent proteolysis of cPLA2 as part of its activation profile. TNFR2, on the other hand, does not cause the phosphorylation of cPLA2 as it does not activate MAPK or p38MAPK, but instead activates cPLA2 by causing its translocation to plasma membrane and perinuclear subcellular regions. TNFR2 activation causes a delayed, slight increase in [Ca2+]i of <50 nM that may contribute towards the translocation and activation of cPLA2. Therefore both TNF receptor subtypes play a role in cPLA2 activation, but by means of separate signal-transduction pathways.
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Chan, Edward D., Brent W. Winston, Soo-Taek Uh, Murry W. Wynes, David M. Rose, and David W. H. Riches. "Evaluation of the Role of Mitogen-Activated Protein Kinases in the Expression of Inducible Nitric Oxide Synthase by IFN-γ and TNF-α in Mouse Macrophages." Journal of Immunology 162, no. 1 (January 1, 1999): 415–22. http://dx.doi.org/10.4049/jimmunol.162.1.415.
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Abstract The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-γ and a number of stimuli, including TNF-α. Recent work has shown that TNF-α activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-γ and TNF-α. All three kinases were activated during costimulation with IFN-γ and TNF-α. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-γ and TNF-α. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-α receptor CD120a (p55) in the presence of IFN-γ.
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Tanaka, Yuji, and Makoto Tsuneoka. "Gallic Acid Derivatives Propyl Gallate and Epigallocatechin Gallate Reduce rRNA Transcription via Induction of KDM2A Activation." Biomolecules 12, no. 1 (December 25, 2021): 30. http://dx.doi.org/10.3390/biom12010030.
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We previously reported that lysine-demethylase 2A (KDM2A), a Jumonji-C histone demethylase, is activated by gallic acid to reduce H3K36me2 levels in the rRNA gene promoter and consequently inhibit rRNA transcription and cell proliferation in the breast cancer cell line MCF-7. Gallic acid activates AMP-activated protein kinase (AMPK) and increases reactive oxygen species (ROS) production to activate KDM2A. Esters of gallic acid, propyl gallate (PG) and epigallocatechin gallate (EGCG), and other chemicals, reduce cancer cell proliferation. However, whether these compounds activate KDM2A has yet to be tested. In this study, we found that PG and EGCG decreased rRNA transcription and cell proliferation through KDM2A in MCF-7 cells. The activation of both AMPK and ROS production by PG or EGCG was required to activate KDM2A. Of note, while the elevation of ROS production by PG or EGCG was limited in time, it was sufficient to activate KDM2A. Importantly, the inhibition of rRNA transcription and cell proliferation by gallic acid, PG, or EGCG was specifically observed in MCF-7 cells, whereas it was not observed in non-tumorigenic MCF10A cells. Altogether, these results suggest that the derivatization of gallic acid may be used to obtain new compounds with anti-cancer activity.
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Yi, Ae-Kyung, and Arthur M. Krieg. "Cutting Edge: Rapid Induction of Mitogen-Activated Protein Kinases by Immune Stimulatory CpG DNA." Journal of Immunology 161, no. 9 (November 1, 1998): 4493–97. http://dx.doi.org/10.4049/jimmunol.161.9.4493.
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Abstract Unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) rapidly activate B cells and monocyte-derived cells; however, the intracellular signaling pathways involved in this process are unclear. Here, we demonstrate that CpG DNA induces the activation of c-Jun NH2-terminal kinase and p38 but does not activate the extracellular receptor kinase in murine B and monocyte-like cell lines. CpG DNA also induces the phosphorylation of activating transcription factor-2, c-Jun, and mitogen-activated protein kinase (MAPK)-activated protein kinase 2 as well as the activation of activator protein-1 (AP-1) DNA binding. Inhibition of p38 led to the suppression of CpG DNA-induced AP-1 DNA-binding activity and cytokine production, indicating that the p38 pathway is required for mediating these immune stimulatory effects of CpG DNA. Chloroquine, an endosomal acidification inhibitor, selectively abolished CpG DNA-mediated MAPK activation. Our results indicate that CpG DNA activates the p38 and c-Jun NH2-terminal kinase MAPK and leads to the activation of AP-1 via a pathway which is sensitive to chloroquine.
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Tang, Yi, Jong Yu, and Jeffrey Field. "Signals from the Ras, Rac, and Rho GTPases Converge on the Pak Protein Kinase in Rat-1 Fibroblasts." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 1881–91. http://dx.doi.org/10.1128/mcb.19.3.1881.
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ABSTRACT Ras plays a key role in regulating cellular proliferation, differentiation, and transformation. Raf is the major effector of Ras in the Ras > Raf > Mek > extracellular signal-activated kinase (ERK) cascade. A second effector is phosphoinositide 3-OH kinase (PI 3-kinase), which, in turn, activates the small G protein Rac. Rac also has multiple effectors, one of which is the serine threonine kinase Pak (p65Pak). Here we show that Ras, but not Raf, activates Pak1 in cotransfection assays of Rat-1 cells but not NIH 3T3 cells. We tested agents that activate or block specific components downstream of Ras and demonstrate a Ras > PI 3-kinase > Rac/Cdc42 > Pak signal. Although these studies suggest that the signal from Ras through PI 3-kinase is sufficient to activate Pak, additional studies suggested that other effectors contribute to Pak activation. RasV12S35 and RasV12G37, two effector mutant proteins which fail to activate PI 3-kinase, did not activate Pak when tested alone but activated Pak when they were cotransfected. Similarly, RacV12H40, an effector mutant that does not bind Pak, and Rho both cooperated with Raf to activate Pak. A dominant negative Rho mutant also inhibited Ras activation of Pak. All combinations of Rac/Raf and Ras/Raf and Rho/Raf effector mutants that transform cells cooperatively stimulated ERK. Cooperation was Pak dependent, since all combinations were inhibited by kinase-deficient Pak mutants in both transformation assays and ERK activation assays. These data suggest that other Ras effectors can collaborate with PI 3-kinase and with each other to activate Pak. Furthermore, the strong correlation between Pak activation and cooperative transformation suggests that Pak activation is necessary, although not sufficient, for cooperative transformation of Rat-1 fibroblasts by Ras, Rac, and Rho.
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Carrozza, M. J., and N. A. DeLuca. "Interaction of the viral activator protein ICP4 with TFIID through TAF250." Molecular and Cellular Biology 16, no. 6 (June 1996): 3085–93. http://dx.doi.org/10.1128/mcb.16.6.3085.
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ICP4 of herpes simplex virus is responsible for the activation of viral transcription during infection. It also efficiently activates and represses transcription in vitro depending on the promoter context. The contacts made between ICP4 and the cellular proteins that result in activated transcription have not been identified. The inability of ICP4 to activate transcription with TATA-binding protein in place of TFIID and the requirement for an initiator element for efficient ICP-4-activated transcription suggest that coactivators, such as TBP-associated factors, are involved (B. Gu and N. DeLuca, J. Virol. 68:7953-7965, 1994). In this study we showed that ICP4 activates transcription in vitro using an immunopurified TFIID, indicating that TBP-associated factors may be a sufficient subset of coactivators for ICP4-activated transcription. Similar to results seen in vivo, the presence of the ICP4 C-terminal region (amino acids 774 to 1298) was important for activation in vitro. With epitope-tagged ICP4 molecules in immunoaffinity experiments, it was shown that the C-terminal region was also required for ICP4 to interact with TFIID present in a crude transcription factor fraction. In the same assay, ICP4 was unable to interact with the basal transcription factors, TFIIB, TFIIE, TFIIF, and TFIIH and RNA polymerase II. ICP4 could also interact with TBP, independent of the C-terminal region. However, reflective of the interaction between ICP4 and TFIID, the ICP4 C-terminal region was required for an interaction with FAF250-TBP complexes and with TAF250 alone. Therefore, the interfaces or conformation of TBP mediating the interaction between ICP4 and TBP in solution is probably masked when TBP is bound to TAF250. With a series of mutant ICP4 molecules purified from herpes simplex virus-infected cells, it was shown that ICP4 molecules that can bind DNA and interact with TAF250 could activate transcription. Taken together, these results demonstrate that ICP4 interaction with TFIID involves the TAF250 molecule and the C-terminal region of ICP4 and that this interaction is part of the mechanism by which ICP4 activates transcription.
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CUENDA, Ana, and Donna S. DOROW. "Differential activation of stress-activated protein kinase kinases SKK4/MKK7 and SKK1/MKK4 by the mixed-lineage kinase-2 and mitogen-activated protein kinase kinase (MKK) kinase-1." Biochemical Journal 333, no. 1 (July 1, 1998): 11–15. http://dx.doi.org/10.1042/bj3330011.
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Overexpression of the protein kinases mixed-lineage kinase-2 (MLK2) or mitogen-activated protein kinase (MAPK) kinase kinase-1 (MEKK1) is known to trigger the activation of stress-activated protein kinase (SAPK1)/c-Jun N-terminal kinase (JNK). Here we demonstrate that MLK2 activates SAPK kinase-1 (SKK1)/MAPK kinase 4 (MKK4) and SKK4/MKK7, the two known direct activators of SAPK1/JNK (both in transfection studies and in vitro). In contrast, MEKK1 activates SKK1/MKK4 more efficiently than MLK2, but barely activates SKK4/MKK7. Since SKK4/MKK7 (but not SKK1/MKK4) is activated by interleukin-1 and tumour necrosis factor in several cells and tissues, we suggest that MEKK1 does not mediate the activation of SKK4/MKK7 and SAPK1/JNK induced by these pro-inflammatory cytokines. MLK2 and MEKK1 also activated SKK2/MKK3 and SKK3/MKK6, the direct upstream activators of SAPK2a/p38.