Articles de revues : « STN8 kinase »

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Rochaix, Jean-David, Sylvain Lemeille, Alexey Shapiguzov, Iga Samol, Geoffrey Fucile, Adrian Willig et Michel Goldschmidt-Clermont. « Protein kinases and phosphatases involved in the acclimation of the photosynthetic apparatus to a changing light environment ». Philosophical Transactions of the Royal Society B : Biological Sciences 367, n^o 1608 (19 décembre 2012) : 3466–74. http://dx.doi.org/10.1098/rstb.2012.0064.

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Photosynthetic organisms are subjected to frequent changes in light quality and quantity and need to respond accordingly. These acclimatory processes are mediated to a large extent through thylakoid protein phosphorylation. Recently, two major thylakoid protein kinases have been identified and characterized. The Stt7/STN7 kinase is mainly involved in the phosphorylation of the LHCII antenna proteins and is required for state transitions. It is firmly associated with the cytochrome b 6 f complex, and its activity is regulated by the redox state of the plastoquinone pool. The other kinase, Stl1/STN8, is responsible for the phosphorylation of the PSII core proteins. Using a reverse genetics approach, we have recently identified the chloroplast PPH1/TAP38 and PBPC protein phosphatases, which counteract the activity of STN7 and STN8 kinases, respectively. They belong to the PP2C-type phosphatase family and are conserved in land plants and algae. The picture that emerges from these studies is that of a complex regulatory network of chloroplast protein kinases and phosphatases that is involved in light acclimation, in maintenance of the plastoquinone redox poise under fluctuating light and in the adjustment to metabolic needs.

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Flood, Pádraic J., Lan Yin, Andrei Herdean, Jeremy Harbinson, Mark G. M. Aarts et Cornelia Spetea. « Natural variation in phosphorylation of photosystem II proteins in Arabidopsis thaliana : is it caused by genetic variation in the STN kinases ? » Philosophical Transactions of the Royal Society B : Biological Sciences 369, n^o 1640 (19 avril 2014) : 20130499. http://dx.doi.org/10.1098/rstb.2013.0499.

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Reversible phosphorylation of photosystem II (PSII) proteins is an important regulatory mechanism that can protect plants from changes in ambient light intensity and quality. We hypothesized that there is natural variation in this process in Arabidopsis ( Arabidopsis thaliana ), and that this results from genetic variation in the STN7 and STN8 kinase genes. To test this, Arabidopsis accessions of diverse geographical origins were exposed to two light regimes, and the levels of phospho-D1 and phospho-light harvesting complex II (LHCII) proteins were quantified by western blotting with anti-phosphothreonine antibodies. Accessions were classified as having high, moderate or low phosphorylation relative to Col-0. This variation could not be explained by the abundance of the substrates in thylakoid membranes. In genotypes with atrazine-resistant forms of the D1 protein, low D1 and LHCII protein phosphorylation was observed, which may be due to low PSII efficiency, resulting in reduced activation of the STN kinases. In the remaining genotypes, phospho-D1 levels correlated with STN8 protein abundance in high-light conditions. In growth light, D1 and LHCII phosphorylation correlated with longitude and in the case of LHCII phosphorylation also with temperature variability. This suggests a possible role of natural variation in PSII protein phosphorylation in the adaptation of Arabidopsis to diverse environments.

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Schönberg, Anna, Anja Rödiger, Wiebke Mehwald, Johann Galonska, Gideon Christ, Stefan Helm, Domenika Thieme, Petra Majovsky, Wolfgang Hoehenwarter et Sacha Baginsky. « Identification of STN7/STN8 kinase targets reveals connections between electron transport, metabolism and gene expression ». Plant Journal 90, n^o 6 (21 avril 2017) : 1176–86. http://dx.doi.org/10.1111/tpj.13536.

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Vainonen, Julia P., Maria Hansson et Alexander V. Vener. « STN8 Protein Kinase inArabidopsis thalianaIs Specific in Phosphorylation of Photosystem II Core Proteins ». Journal of Biological Chemistry 280, n^o 39 (22 juillet 2005) : 33679–86. http://dx.doi.org/10.1074/jbc.m505729200.

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Gerotto, Caterina, Andrea Trotta, Azfar Ali Bajwa, Ilaria Mancini, Tomas Morosinotto et Eva-Mari Aro. « Thylakoid Protein Phosphorylation Dynamics in a Moss Mutant Lacking SERINE/THREONINE PROTEIN KINASE STN8 ». Plant Physiology 180, n^o 3 (6 mai 2019) : 1582–97. http://dx.doi.org/10.1104/pp.19.00117.

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Reiland, S., G. Finazzi, A. Endler, A. Willig, K. Baerenfaller, J. Grossmann, B. Gerrits et al. « Comparative phosphoproteome profiling reveals a function of the STN8 kinase in fine-tuning of cyclic electron flow (CEF) ». Proceedings of the National Academy of Sciences 108, n^o 31 (18 juillet 2011) : 12955–60. http://dx.doi.org/10.1073/pnas.1104734108.

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Poudyal, Roshan Sharma, Krishna Nath, Ismayil S. Zulfugarov et Choon-Hwan Lee. « Production of superoxide from photosystem II-light harvesting complex II supercomplex in STN8 kinase knock-out rice mutants under photoinhibitory illumination ». Journal of Photochemistry and Photobiology B : Biology 162 (septembre 2016) : 240–47. http://dx.doi.org/10.1016/j.jphotobiol.2016.06.050.

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Betterle, Nico, Roshan Sharma Poudyal, Anthony Rosa, Guangxi Wu, Roberto Bassi et Choon-Hwan Lee. « The STN8 kinase-PBCP phosphatase system is responsible for high-light-induced reversible phosphorylation of the PSII inner antenna subunit CP29 in rice ». Plant Journal 89, n^o 4 (février 2017) : 681–91. http://dx.doi.org/10.1111/tpj.13412.

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Wu, Jianghao, Liwei Rong, Weijun Lin, Lingxi Kong, Dengjie Wei, Lixin Zhang, Jean-David Rochaix et Xiumei Xu. « Functional redox links between lumen thiol oxidoreductase1 and serine/threonine-protein kinase STN7 ». Plant Physiology 186, n^o 2 (23 février 2021) : 964–76. http://dx.doi.org/10.1093/plphys/kiab091.

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Abstract In response to changing light quantity and quality, photosynthetic organisms perform state transitions, a process which optimizes photosynthetic yield and mitigates photo-damage. The serine/threonine-protein kinase STN7 phosphorylates the light-harvesting complex of photosystem II (PSII; light-harvesting complex II), which then migrates from PSII to photosystem I (PSI), thereby rebalancing the light excitation energy between the photosystems and restoring the redox poise of the photosynthetic electron transport chain. Two conserved cysteines forming intra- or intermolecular disulfide bonds in the lumenal domain (LD) of STN7 are essential for the kinase activity although it is still unknown how activation of the kinase is regulated. In this study, we show lumen thiol oxidoreductase 1 (LTO1) is co-expressed with STN7 in Arabidopsis (Arabidopsis thaliana) and interacts with the LD of STN7 in vitro and in vivo. LTO1 contains thioredoxin (TRX)-like and vitamin K epoxide reductase domains which are related to the disulfide-bond formation system in bacteria. We further show that the TRX-like domain of LTO1 is able to oxidize the conserved lumenal cysteines of STN7 in vitro. In addition, loss of LTO1 affects the kinase activity of STN7 in Arabidopsis. Based on these results, we propose that LTO1 helps to maintain STN7 in an oxidized active state in state 2 through redox interactions between the lumenal cysteines of STN7 and LTO1.

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Eisa, Ahmed, Bettina Bölter et Serena Schwenkert. « The ACT domain in chloroplast precursor–phosphorylating STY kinases binds metabolites and allosterically regulates kinase activity ». Journal of Biological Chemistry 294, n^o 46 (8 octobre 2019) : 17278–88. http://dx.doi.org/10.1074/jbc.ra119.010298.

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Protein import of nucleus-encoded proteins into plant chloroplasts is a highly regulated process, requiring fine-tuning mechanisms especially during chloroplast differentiation. One way of altering import efficiency is phosphorylation of chloroplast transit peptides in the cytosol. We recently investigated the role of three serine/threonine/tyrosine (STY) kinases, STY8, STY17, and STY46, in precursor phosphorylation. These three kinases have a high degree of similarity and harbor a conserved aspartate kinase–chorismate mutase–tyrA (prephenate dehydrogenase) (ACT) domain upstream of the kinase domain. The ACT domain is a widely distributed structural motif known to be important for allosteric regulation of many enzymes. In this work, using biochemical and biophysical techniques in vitro and in planta, including kinase assays, microscale thermophoresis, size exclusion chromatography, as well as site-directed mutagenesis approaches, we show that the ACT domain regulates autophosphorylation and substrate phosphorylation of the STY kinases. We found that isoleucine and S-adenosylmethionine bind to the ACT domain, negatively influencing its autophosphorylation ability. Moreover, we investigated the role of the ACT domain in planta and confirmed its involvement in chloroplast differentiation in vivo. Our results provide detailed insights into the regulation of enzyme activity by ACT domains and establish that it has a role in binding amino acid ligands during chloroplast biogenesis.

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Gasparayan, Hovik, Chris Caridi, Jeff Julius, Wenyi Feng, Jeff Bachant et Constance I. Nugent. « Yeast Stn1 promotes MCM to circumvent Rad53 control of the S phase checkpoint ». Current Genetics 68, n^o 2 (12 février 2022) : 165–79. http://dx.doi.org/10.1007/s00294-022-01228-0.

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AbstractTreating yeast cells with the replication inhibitor hydroxyurea activates the S phase checkpoint kinase Rad53, eliciting responses that block DNA replication origin firing, stabilize replication forks, and prevent premature extension of the mitotic spindle. We previously found overproduction of Stn1, a subunit of the telomere-binding Cdc13–Stn1–Ten1 complex, circumvents Rad53 checkpoint functions in hydroxyurea, inducing late origin firing and premature spindle extension even though Rad53 is activated normally. Here, we show Stn1 overproduction acts through remarkably similar pathways compared to loss of RAD53, converging on the MCM complex that initiates origin firing and forms the catalytic core of the replicative DNA helicase. First, mutations affecting Mcm2 and Mcm5 block the ability of Stn1 overproduction to disrupt the S phase checkpoint. Second, loss of function stn1 mutations compensate rad53 S phase checkpoint defects. Third Stn1 overproduction suppresses a mutation in Mcm7. Fourth, stn1 mutants accumulate single-stranded DNA at non-telomeric genome locations, imposing a requirement for post-replication DNA repair. We discuss these interactions in terms of a model in which Stn1 acts as an accessory replication factor that facilitates MCM activation at ORIs and potentially also maintains MCM activity at replication forks advancing through challenging templates.

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Johnson, Matthew P. « Metabolic regulation of photosynthetic membrane structure tunes electron transfer function ». Biochemical Journal 475, n^o 7 (5 avril 2018) : 1225–33. http://dx.doi.org/10.1042/bcj20170526.

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The photosynthetic chloroplast thylakoid membrane of higher plants is a complex three-dimensional structure that is morphologically dynamic on a timescale of just a few minutes. The membrane dynamics are driven by the phosphorylation of light-harvesting complex II (LHCII) by the STN7 kinase, which controls the size of the stacked grana region relative to the unstacked stromal lamellae region. Here, I hypothesise that the functional significance of these membrane dynamics is in controlling the partition of electrons between photosynthetic linear and cyclic electron transfer (LET and CET), which determines the ratio of NADPH/ATP produced. The STN7 kinase responds to the metabolic state of the chloroplast by sensing the stromal redox state. A high NADPH/ATP ratio leads to reduction of thioredoxin f (TRXf), which reduces a CxxxC motif in the stromal domain of STN7 leading to its inactivation, whereas a low NADPH/ATP ratio leads to oxidation of TRXf and STN7 activation. Phosphorylation of LHCII leads to smaller grana, which favour LET by speeding up diffusion of electron carriers plastoquinone (PQ) and plastocyanin (PC) between the domains. In contrast, dephosphorylation of LHCII leads to larger grana that slow the diffusion of PQ and PC, leaving the PQ pool in the stroma more oxidised, thus enhancing the efficiency of CET. The feedback regulation of electron transfer by the downstream metabolism is crucial to plant fitness, since perturbations in the NADPH/ATP ratio can rapidly lead to the inhibition of photosynthesis and photo-oxidative stress.

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Węgrzyn, Anna, Małgorzata Krysiak, Anna Kulik, Katarzyna B. Gieczewska et Radosław Mazur. « STN7 Kinase Is Essential for Arabidopsis thaliana Fitness under Prolonged Darkness but Not under Dark-Chilling Conditions ». International Journal of Molecular Sciences 23, n^o 9 (20 avril 2022) : 4531. http://dx.doi.org/10.3390/ijms23094531.

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Reversible phosphorylation of photosystem II light harvesting complexes (LHCII) is a well-established protective mechanism enabling efficient response to changing light conditions. However, changes in LHCII phosphorylation were also observed in response to abiotic stress regardless of photoperiod. This study aimed to investigate the impact of dark-chilling on LHCII phosphorylation pattern in chilling-tolerant Arabidopsis thaliana and to check whether the disturbed LHCII phosphorylation process will impact the response of Arabidopsis to the dark-chilling conditions. We analyzed the pattern of LHCII phosphorylation, the organization of chlorophyll–protein complexes, and the level of chilling tolerance by combining biochemical and spectroscopy techniques under dark-chilling and dark conditions in Arabidopsis mutants with disrupted LHCII phosphorylation. Our results show that during dark-chilling, LHCII phosphorylation decreased in all examined plant lines and that no significant differences in dark-chilling response were registered in tested lines. Interestingly, after 24 h of darkness, a high increase in LHCII phosphorylation was observed, co-occurring with a significant FV/FM parameter decrease. The highest drop of FV/FM was detected in the stn7-1 line–mutant, where the LHCII is not phosphorylated, due to the lack of STN7 kinase. Our results imply that STN7 kinase activity is important for mitigating the adverse effects of prolonged darkness.

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Bellafiore, Stéphane, Frédy Barneche, Gilles Peltier et Jean-David Rochaix. « State transitions and light adaptation require chloroplast thylakoid protein kinase STN7 ». Nature 433, n^o 7028 (février 2005) : 892–95. http://dx.doi.org/10.1038/nature03286.

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Nikovits, W., J. H. Mar et C. P. Ordahl. « Muscle-specific activity of the skeletal troponin I promoter requires interaction between upstream regulatory sequences and elements contained within the first transcribed exon ». Molecular and Cellular Biology 10, n^o 7 (juillet 1990) : 3468–82. http://dx.doi.org/10.1128/mcb.10.7.3468-3482.1990.

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Expression of the skeletal troponin I (sTnI) gene is regulated transcriptionally in a muscle-specific fashion. We show here that the region of the sTnI gene between -160 and +61 (relative to the transcription initiation site) is able to direct expression of the bacterial chloramphenicol acetyltransferase (CAT) gene is muscle cultures at a level approximately 100 times higher than in fibroblast cultures. RNA analysis demonstrated that transcription of the CAT gene was initiated at the same site as transcription of the endogenous sTnI gene and that CAT activity levels were approximately proportional to CAT mRNA levels. Deletion analysis demonstrated that the region between nucleotides -160 and -40 contained sequences essential for full promoter activity. Surprisingly, 3' deletion analysis indicated that the first exon (-6 to +61) of the sTnI gene was also required for full activity of the sTnI promoter in skeletal muscle cells. Chimeric promoter experiments, in which segments of the sTnI and the herpes simplex virus thymidine kinase promoter were interchanged, indicated that reconstitution of a muscle-specific promoter required inclusion of both the upstream and exon I regions of the sTnI gene. Exon I, and the region immediately upstream, showed DNase protection over sequence motifs related to those found in other genes, including the tar region of human immunodeficiency virus type 1. These results demonstrate that expression of the sTnI promoter in embryonic skeletal muscle cells requires complex interaction between two separate promoter regions, one of which resides within the first 61 transcribed nucleotides of the gene.

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Nikovits, W., J. H. Mar et C. P. Ordahl. « Muscle-specific activity of the skeletal troponin I promoter requires interaction between upstream regulatory sequences and elements contained within the first transcribed exon. » Molecular and Cellular Biology 10, n^o 7 (juillet 1990) : 3468–82. http://dx.doi.org/10.1128/mcb.10.7.3468.

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Expression of the skeletal troponin I (sTnI) gene is regulated transcriptionally in a muscle-specific fashion. We show here that the region of the sTnI gene between -160 and +61 (relative to the transcription initiation site) is able to direct expression of the bacterial chloramphenicol acetyltransferase (CAT) gene is muscle cultures at a level approximately 100 times higher than in fibroblast cultures. RNA analysis demonstrated that transcription of the CAT gene was initiated at the same site as transcription of the endogenous sTnI gene and that CAT activity levels were approximately proportional to CAT mRNA levels. Deletion analysis demonstrated that the region between nucleotides -160 and -40 contained sequences essential for full promoter activity. Surprisingly, 3' deletion analysis indicated that the first exon (-6 to +61) of the sTnI gene was also required for full activity of the sTnI promoter in skeletal muscle cells. Chimeric promoter experiments, in which segments of the sTnI and the herpes simplex virus thymidine kinase promoter were interchanged, indicated that reconstitution of a muscle-specific promoter required inclusion of both the upstream and exon I regions of the sTnI gene. Exon I, and the region immediately upstream, showed DNase protection over sequence motifs related to those found in other genes, including the tar region of human immunodeficiency virus type 1. These results demonstrate that expression of the sTnI promoter in embryonic skeletal muscle cells requires complex interaction between two separate promoter regions, one of which resides within the first 61 transcribed nucleotides of the gene.

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Achuthan, Adrian, Paul Masendycz, Jamie A. Lopez, Thao Nguyen, David E. James, Matthew J. Sweet, John A. Hamilton et Glen M. Scholz. « Regulation of the Endosomal SNARE Protein Syntaxin 7 by Colony-Stimulating Factor 1 in Macrophages ». Molecular and Cellular Biology 28, n^o 20 (18 août 2008) : 6149–59. http://dx.doi.org/10.1128/mcb.00220-08.

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ABSTRACT Colony-stimulating factor 1 (CSF-1) is the main growth factor controlling the development of macrophages from myeloid progenitor cells. However, CSF-1 also regulates some of the key effector functions of macrophages (e.g., phagocytosis and cytokine secretion). The endosomal SNARE protein syntaxin 7 (Stx7) regulates vesicle trafficking events involved in phagocytosis and cytokine secretion. Therefore, we investigated the ability of CSF-1 to regulate Stx7. CSF-1 upregulated Stx7 expression in primary mouse macrophages; it also upregulated expression of its SNARE partners Vti1b and VAMP8 but not Stx8. Additionally, CSF-1 induced the rapid serine phosphorylation of Stx7 and enhanced its binding to Vti1b, Stx8, and VAMP8. Bioinformatics analysis and results from experiments with kinase inhibitors suggested the CSF-1-induced phosphorylation of Stx7 was mediated by protein kinase C and Akt in response to phosphatidylinositol 3-kinase activation. Based on mutagenesis studies, CSF-1 appeared to increase the binding of Stx7 to its SNARE partners by inducing the phosphorylation of serine residues in the Habc domain and/or “linker” region of Stx7. Thus, CSF-1 is a key regulator of Stx7 expression and function in macrophages. Furthermore, the effects of CSF-1 on Stx7 may provide a mechanism for the regulation of macrophage effector functions by CSF-1.

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Sorichter, Stephan, Johannes Mair, Arnold Koller, Walter Gebert, Daniel Rama, Charles Calzolari, Erika Artner-Dworzak et Bernd Puschendorf. « Skeletal troponin I as a marker of exercise-induced muscle damage ». Journal of Applied Physiology 83, n^o 4 (1 octobre 1997) : 1076–82. http://dx.doi.org/10.1152/jappl.1997.83.4.1076.

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Sorichter, Stephan, Johannes Mair, Arnold Koller, Walter Gebert, Daniel Rama, Charles Calzolari, Erika Artner-Dworzak, and Bernd Puschendorf. Skeletal troponin I as a marker of exercise-induced muscle damage. J. Appl. Physiol.83(4): 1076–1082, 1997.—The utility of skeletal troponin I (sTnI) as a plasma marker of skeletal muscle damage after exercise was compared against creatine kinase (CK), myoglobin (Mb), and myosin heavy chain (MHC) fragments. These markers were serially measured in normal physical education teacher trainees after four different exercise regimens: 20 min of level or downhill (16% decline) running (intensity: 70% maximal O2uptake), high-force eccentric contractions (70 repetitions), or high-force isokinetic concentric contractions of the quadriceps group (40 repetitions). Eccentrically biased exercise (downhill running and eccentric contractions) promoted greater increases in all parameters. The highest plasma concentration were found after downhill running {median peaks: 309 U/l CK concentration ([CK])}, 466 μg/l Mb concentration ([Mb]), 1,021 μU/l MHC concentration ([MHC]), and 27.3 μg/l sTnI concentration ([sTnI]). Level running produced a moderate response (median peaks: 178 U/l [CK], 98 μg/l [Mb], 501 μU/l [MHC], and 6.6 μg/l [sTnI]), whereas the concentric contraction protocol did not elicit significant changes in any of the markers assayed. sTnI increased and peaked in parallel to CK and stayed elevated (>2.2 μg/l) for at least 1–2 days after exercise. In contrast to MHC, sTnI is an initial, specific marker of exercise-induced muscle injury, which may be partly explained by their different intracellular compartmentation with essentially no (MHC <0.1%) or a small soluble pool (sTnI: median 3.4%).

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Pesaresi, Paolo, Alexander Hertle, Mathias Pribil, Tatjana Kleine, Raik Wagner, Henning Strissel, Anna Ihnatowicz et al. « Arabidopsis STN7 Kinase Provides a Link between Short- and Long-Term Photosynthetic Acclimation ». Plant Cell 21, n^o 8 (août 2009) : 2402–23. http://dx.doi.org/10.1105/tpc.108.064964.

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Shapiguzov, Alexey, Xin Chai, Geoffrey Fucile, Paolo Longoni, Lixin Zhang et Jean-David Rochaix. « Activation of the Stt7/STN7 Kinase through Dynamic Interactions with the Cytochrome b6f Complex ». Plant Physiology 171, n^o 1 (3 mars 2016) : 82–92. http://dx.doi.org/10.1104/pp.15.01893.

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Willig, Adrian, Alexey Shapiguzov, Michel Goldschmidt-Clermont et Jean-David Rochaix. « The Phosphorylation Status of the Chloroplast Protein Kinase STN7 of Arabidopsis Affects Its Turnover ». Plant Physiology 157, n^o 4 (5 octobre 2011) : 2102–7. http://dx.doi.org/10.1104/pp.111.187328.

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Ingelsson, Björn, et Alexander V. Vener. « Phosphoproteomics ofArabidopsischloroplasts reveals involvement of the STN7 kinase in phosphorylation of nucleoid protein pTAC16 ». FEBS Letters 586, n^o 9 (10 avril 2012) : 1265–71. http://dx.doi.org/10.1016/j.febslet.2012.03.061.

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Yu, Liming, Qing Li, Bo Yu, Yang Yang, Zhenxiao Jin, Weixun Duan, Guolong Zhao et al. « Berberine Attenuates Myocardial Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Inflammation Response : Role of Silent Information Regulator 1 ». Oxidative Medicine and Cellular Longevity 2016 (2016) : 1–16. http://dx.doi.org/10.1155/2016/1689602.

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Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91phoxexpression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

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Ancín, María, Alicia Fernández-San Millán, Luis Larraya, Fermín Morales, Jon Veramendi, Iker Aranjuelo et Inmaculada Farran. « Overexpression of thioredoxin m in tobacco chloroplasts inhibits the protein kinase STN7 and alters photosynthetic performance ». Journal of Experimental Botany 70, n^o 3 (21 novembre 2018) : 1005–16. http://dx.doi.org/10.1093/jxb/ery415.

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Lamberti, Giorgia, Irene L. Gügel, Jörg Meurer, Jürgen Soll et Serena Schwenkert. « The Cytosolic Kinases STY8, STY17, and STY46 Are Involved in Chloroplast Differentiation in Arabidopsis ». Plant Physiology 157, n^o 1 (28 juillet 2011) : 70–85. http://dx.doi.org/10.1104/pp.111.182774.

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Matsumura, Cíntia Yuri, Ana Paula Tiemi Taniguti, Adriana Pertille, Humberto Santo Neto et Maria Julia Marques. « Stretch-activated calcium channel protein TRPC1 is correlated with the different degrees of the dystrophic phenotype in mdx mice ». American Journal of Physiology-Cell Physiology 301, n^o 6 (décembre 2011) : C1344—C1350. http://dx.doi.org/10.1152/ajpcell.00056.2011.

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In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin is related to enhanced calcium influx and muscle degeneration. Stretch-activated channels (SACs) might be directly involved in the pathology of DMD, and transient receptor potential cation channels have been proposed as likely candidates of SACs. We investigated the levels of transient receptor potential canonical channel 1 (TRPC1) and the effects of streptomycin, a SAC blocker, in muscles showing different degrees of the dystrophic phenotype. Mdx mice (18 days old, n = 16) received daily intraperitoneal injections of streptomycin (182 mg/kg body wt) for 18 days, followed by removal of the diaphragm, sternomastoid (STN), biceps brachii, and tibialis anterior muscles. Control mdx mice ( n = 37) were injected with saline. Western blot analysis showed higher levels of TRPC1 in diaphragm muscle compared with STN and limb muscles. Streptomycin reduced creatine kinase and prevented exercise-induced increases of total calcium and Evans blue dye uptake in diaphragm and in STN muscles. It is suggested that different levels of the stretch-activated calcium channel protein TRPC1 may contribute to the different degrees of the dystrophic phenotype seen in mdx mice. Early treatment designed to regulate the activity of these channels may ameliorate the progression of dystrophy in the most affected muscle, the diaphragm.

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Osmond, Barry, Wah Soon Chow, Barry J. Pogson et Sharon A. Robinson. « Probing functional and optical cross-sections of PSII in leaves during state transitions using fast repetition rate light induced fluorescence transients ». Functional Plant Biology 46, n^o 6 (2019) : 567. http://dx.doi.org/10.1071/fp18054.

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Plants adjust the relative sizes of PSII and PSI antennae in response to the spectral composition of weak light favouring either photosystem by processes known as state transitions (ST), attributed to a discrete antenna migration involving phosphorylation of light-harvesting chlorophyll-protein complexes in PSII. Here for the first time we monitored the extent and dynamics of ST in leaves from estimates of optical absorption cross-section (relative PSII antenna size; aPSII). These estimates were obtained from in situ measurements of functional absorption cross-section (σPSII) and maximum photochemical efficiency of PSII (φPSII); i.e. aPSII = σPSII/φPSII (Kolber et al. 1998) and other parameters from a light induced fluorescence transient (LIFT) device (Osmond et al. 2017). The fast repetition rate (FRR) QA flash protocol of this instrument monitors chlorophyll fluorescence yields with reduced QA irrespective of the redox state of plastoquinone (PQ), as well as during strong ~1 s white light pulses that fully reduce the PQ pool. Fitting this transient with the FRR model monitors kinetics of PSII → PQ, PQ → PSI, and the redox state of the PQ pool in the ‘PQ pool control loop’ that underpins ST, with a time resolution of a few seconds. All LIFT/FRR criteria confirmed the absence of ST in antenna mutant chlorina-f2 of barley and asLhcb2–12 of Arabidopsis, as well as STN7 kinase mutants stn7 and stn7/8. In contrast, wild-type barley and Arabidopsis genotypes Col, npq1, npq4, OEpsbs, pgr5 bkg and pgr5, showed normal ST. However, the extent of ST (and by implication the size of the phosphorylated LHCII pool participating in ST) deduced from changes in aʹPSII and other parameters with reduced QA range up to 35%. Estimates from strong WL pulses in the same assay were only ~10%. The larger estimates of ST from the QA flash are discussed in the context of contemporary dynamic structural models of ST involving formation and participation of PSII and PSI megacomplexes in an ‘energetically connected lake’ of phosphorylated LHCII trimers (Grieco et al. 2015). Despite the absence of ST, asLhcb2-12 displays normal wild-type modulation of electron transport rate (ETR) and the PQ pool during ST assays, reflecting compensatory changes in antenna LHCIIs in this genotype. Impaired LHCII phosphorylation in stn7 and stn7/8 accelerates ETR from PSII →PQ, over-reducing the PQ pool and abolishing the yield difference between the QA flash and WL pulse, with implications for photochemical and thermal phases of the O-J-I-P transient.

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Matsuba, Douchi, Takako Terui, Jin O-Uchi, Hiroyuki Tanaka, Takao Ojima, Iwao Ohtsuki, Shin'ichi Ishiwata, Satoshi Kurihara et Norio Fukuda. « Protein kinase A–dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponin ». Journal of General Physiology 133, n^o 6 (11 mai 2009) : 571–81. http://dx.doi.org/10.1085/jgp.200910206.

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Protein kinase A (PKA)-dependent phosphorylation of troponin (Tn)I represents a major physiological mechanism during β-adrenergic stimulation in myocardium for the reduction of myofibrillar Ca2+ sensitivity via weakening of the interaction with TnC. By taking advantage of thin filament reconstitution, we directly investigated whether or not PKA-dependent phosphorylation of cardiac TnI (cTnI) decreases Ca2+ sensitivity in different types of muscle: cardiac (porcine ventricular) and fast skeletal (rabbit psoas) muscles. PKA enhanced phosphorylation of cTnI at Ser23/24 in skinned cardiac muscle and decreased Ca2+ sensitivity, of which the effects were confirmed after reconstitution with the cardiac Tn complex (cTn) or the hybrid Tn complex (designated as PCRF; fast skeletal TnT with cTnI and cTnC). Reconstitution of cardiac muscle with the fast skeletal Tn complex (sTn) not only increased Ca2+ sensitivity, but also abolished the Ca2+-desensitizing effect of PKA, supporting the view that the phosphorylation of cTnI, but not that of other myofibrillar proteins, such as myosin-binding protein C, primarily underlies the PKA-induced Ca2+ desensitization in cardiac muscle. Reconstitution of fast skeletal muscle with cTn decreased Ca2+ sensitivity, and PKA further decreased Ca2+ sensitivity, which was almost completely restored to the original level upon subsequent reconstitution with sTn. The essentially same result was obtained when fast skeletal muscle was reconstituted with PCRF. It is therefore suggested that the PKA-dependent phosphorylation or dephosphorylation of cTnI universally modulates Ca2+ sensitivity associated with cTnC in the striated muscle sarcomere, independent of the TnT isoform.

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Styrkársdóttir, Unnur, Richard Egel et Olaf Nielsen. « Functional conservation between Schizosaccharomyces pombe ste8 and Saccharomyces cerevisiae STE11 protein kinases in yeast signal transduction ». Molecular and General Genetics MGG 235, n^o 1 (octobre 1992) : 122–30. http://dx.doi.org/10.1007/bf00286189.

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Langlands-Perry, Camilla, Murielle Cuenin, Christophe Bergez, Safa Ben Krima, Sandrine Gélisse, Pierre Sourdille, Romain Valade et Thierry C. Marcel. « Resistance of the Wheat Cultivar ‘Renan’ to Septoria Leaf Blotch Explained by a Combination of Strain Specific and Strain Non-Specific QTL Mapped on an Ultra-Dense Genetic Map ». Genes 13, n^o 1 (31 décembre 2021) : 100. http://dx.doi.org/10.3390/genes13010100.

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Quantitative resistance is considered more durable than qualitative resistance as it does not involve major resistance genes that can be easily overcome by pathogen populations, but rather a combination of genes with a lower individual effect. This durability means that quantitative resistance could be an interesting tool for breeding crops that would not systematically require phytosanitary products. Quantitative resistance has yet to reveal all of its intricacies. Here, we delve into the case of the wheat/Septoria tritici blotch (STB) pathosystem. Using a population resulting from a cross between French cultivar Renan, generally resistant to STB, and Chinese Spring, a cultivar susceptible to the disease, we built an ultra-dense genetic map that carries 148,820 single nucleotide polymorphism (SNP) markers. Phenotyping the interaction was done with two different Zymoseptoria tritici strains with contrasted pathogenicities on Renan. A linkage analysis led to the detection of three quantitative trait loci (QTL) related to resistance in Renan. These QTL, on chromosomes 7B, 1D, and 5D, present with an interesting diversity as that on 7B was detected with both fungal strains, while those on 1D and 5D were strain-specific. The resistance on 7B was located in the region of Stb8 and the resistance on 1D colocalized with Stb19. However, the resistance on 5D was new, so further designated Stb20q. Several wall-associated kinases (WAK), nucleotide-binding and leucine-rich repeats (NB-LRR) type, and kinase domain carrying genes were present in the QTL regions, and some of them were expressed during the infection. These results advocate for a role of Stb genes in quantitative resistance and for resistance in the wheat/STB pathosystem being as a whole quantitative and polygenic.

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Wang, Y., H. P. Xu, M. Riggs, L. Rodgers et M. Wigler. « byr2, a Schizosaccharomyces pombe gene encoding a protein kinase capable of partial suppression of the ras1 mutant phenotype ». Molecular and Cellular Biology 11, n^o 7 (juillet 1991) : 3554–63. http://dx.doi.org/10.1128/mcb.11.7.3554-3563.1991.

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Schizosaccharomyces pombe contains a single gene, ras1, which is a homolog of the mammalian RAS genes. ras1 is required for conjugation, sporulation, and normal cell shape. ras1 has been previously identified as ste5. We report here a gene we call byr2 that can encode a predicted protein kinase and can partially suppress defects in ras1 mutants. ras1 mutant strains expressing high levels of byr2 can sporulate competently but are still defective in conjugation and abnormally round. byr2 mutants are viable and have normal shape but are absolutely defective in conjugation and sporulation. byr2 is probably identical to ste8. In many respects, byr2 resembles the byr1 gene, another suppressor of the ras1 mutation, which has been identified previously as ste1. Our data indicate that if ras1, byr2, and byr1 act along the same pathway, then the site of action for byr2 is between the sites for ras1 and byr1.

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Wang, Y., H. P. Xu, M. Riggs, L. Rodgers et M. Wigler. « byr2, a Schizosaccharomyces pombe gene encoding a protein kinase capable of partial suppression of the ras1 mutant phenotype. » Molecular and Cellular Biology 11, n^o 7 (juillet 1991) : 3554–63. http://dx.doi.org/10.1128/mcb.11.7.3554.

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Schizosaccharomyces pombe contains a single gene, ras1, which is a homolog of the mammalian RAS genes. ras1 is required for conjugation, sporulation, and normal cell shape. ras1 has been previously identified as ste5. We report here a gene we call byr2 that can encode a predicted protein kinase and can partially suppress defects in ras1 mutants. ras1 mutant strains expressing high levels of byr2 can sporulate competently but are still defective in conjugation and abnormally round. byr2 mutants are viable and have normal shape but are absolutely defective in conjugation and sporulation. byr2 is probably identical to ste8. In many respects, byr2 resembles the byr1 gene, another suppressor of the ras1 mutation, which has been identified previously as ste1. Our data indicate that if ras1, byr2, and byr1 act along the same pathway, then the site of action for byr2 is between the sites for ras1 and byr1.

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TEK, Mumin Ibrahim, et Ozer CALIS. « Mechanisms of resistance to powdery mildew in cucumber ». Phytopathologia Mediterranea 61, n^o 1 (13 mai 2022) : 119–27. http://dx.doi.org/10.36253/phyto-13313.

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Podosphaera xanthii causes powdery mildew of cucumber, and is associated with significant yield and quality losses. Development of resistant or tolerant varieties is the most effective and eco-friendly strategy for powdery mildew management. An important host resistance mechanism is based on the recognition of conserved resistance genes, resulting in durable resistance. To determine powdery mildew resistance mechanisms in cucumber, total RNAs were isolated from the powdery mildew resistant cultivar Meltem, the tolerant line VT18, and the susceptible local variety Camlica. Expression levels of nine genes in these plants were analysed by Reverse Transcription Polymerase Chain Reaction (RT-PCR). The host reactions were assessed using microscope observations of stained specimens. Serine/threonine (STN7), transcription factor (WRKY22), serine/threonine-protein kinase (D6PKL1), and serine/threonine receptor kinase (NFP) genes were induced, as positive regulators in defence mechanisms against powdery mildew. Polygalacturonase Inhibitor (PGIP) did not express after P. xanthii inoculation of Camlica, resulting in susceptibility. After inoculation, callose synthase (CALLOSE) and cinnamyl alcohol dehydrogenase (CAD) gene expression levels were increased in resistant Meltem, but Hypersensitive Reaction (HR) and ROS formation were only linked in the tolerant VT18. Powdery mildew development was less in Meltem than in VT18, indicating that cell wall thickening and HR play separate roles in resistance to this disease.

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Khodabukus, Alastair, Amulya Kaza, Jason Wang, Neel Prabhu, Richard Goldstein, Vishal S. Vaidya et Nenad Bursac. « Tissue-Engineered Human Myobundle System as a Platform for Evaluation of Skeletal Muscle Injury Biomarkers ». Toxicological Sciences 176, n^o 1 (6 mai 2020) : 124–36. http://dx.doi.org/10.1093/toxsci/kfaa049.

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Abstract Traditional serum biomarkers used to assess skeletal muscle damage, such as activity of creatine kinase (CK), lack tissue specificity and sensitivity, hindering early detection of drug-induced myopathies. Recently, a novel four-factor skeletal muscle injury panel (MIP) of biomarkers consisting of skeletal troponin I (sTnI), CK mass (CKm), fatty-acid-binding protein 3 (Fabp3), and myosin light chain 3, has been shown to have increased tissue specificity and sensitivity in rodent models of skeletal muscle injury. Here, we evaluated if a previously established model of tissue-engineered functional human skeletal muscle (myobundle) can allow detection of the MIP biomarkers after injury or drug-induced myotoxicity in vitro. We found that concentrations of three MIP biomarkers (sTnI, CKm, and Fabp3) in myobundle culture media significantly increased in response to injury by a known snake venom (notexin). Cerivastatin, a known myotoxic statin, but not pravastatin, induced significant loss of myobundle contractile function, myotube atrophy, and increased release of both traditional and novel biomarkers. In contrast, dexamethasone induced significant loss of myobundle contractile function and myotube atrophy, but decreased the release of both traditional and novel biomarkers. Dexamethasone also increased levels of matrix metalloproteinase-2 and -3 in the culture media which correlated with increased remodeling of myobundle extracellular matrix. In conclusion, this proof-of-concept study demonstrates that tissue-engineered human myobundles can provide an in vitro platform to probe patient-specific drug-induced myotoxicity and performance assessment of novel injury biomarkers to guide preclinical and clinical drug development studies.

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Trotta, Andrea, Marjaana Suorsa, Marjaana Rantala, Björn Lundin et Eva‐Mari Aro. « Serine and threonine residues of plant STN 7 kinase are differentially phosphorylated upon changing light conditions and specifically influence the activity and stability of the kinase ». Plant Journal 87, n^o 5 (2 août 2016) : 484–94. http://dx.doi.org/10.1111/tpj.13213.

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Kim, Jong Hyun, Taek-Hyun Kwon, Seong-Beom Koh et Jung Youl Park. « Parkinsonism-Hyperpyrexia Syndrome After Deep Brain Stimulation Surgery ». Neurosurgery 66, n^o 5 (1 mai 2010) : E1029. http://dx.doi.org/10.1227/01.neu.0000367799.38332.43.

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Abstract OBJECTIVE Deep brain stimulation is an alternative treatment for advanced Parkinson's disease. Levodopa medications are usually discontinued the night before surgery to localize the optimal response site to intraoperative macrostimulation. However, abrupt withdrawal of medication may result in side effects. We report a case of parkinsonism-hyperpyrexia syndrome (PHS), a rare complication resulting from discontinuation of antiparkinsonian medication, after a deep brain stimulation (DBS) procedure for bilateral subthalamic-nucleus (STN). CLINICAL PRESENTATION A 66-year-old woman with an 11-year history of idiopathic Parkinson's disease was admitted for DBS. She had experienced wearing-off symptoms, severe peak-dose dyskinesia, and medication-induced side effects. Antiparkinsonian medication was discontinued 2 days before surgery because of severe drug-related complications. DBS for bilateral STN was performed uneventfully, but the patient was unconscious with fever, tachycardia, and hypertension after surgery. INTERVENTION Levodopa and dopamine agonist replacement by nasogastric tube and hydration were immediately administered with conservative treatment for the hypertension, tachycardia, and fever. The patient's serum creatine kinase level increased to 786 U/L 3 days after the surgery and then decreased gradually as the patient's consciousness improved. CONCLUSION Physicians should be aware of the possibility of PHS after a deep brain stimulation procedure. If the patient shows unexplained changes in consciousness with hyperpyrexia after surgery, PHS should be considered and adequate treatment should be given immediately to prevent death.

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Rajesh, Christabelle, Satish Sagar, Ashok Kumar Rathinavel, Divya Thomas Chemparathy, Xianlu Laura Peng, Jen Jen Yeh, Michael A. Hollingsworth et Prakash Radhakrishnan. « Truncated O-Glycan-Bearing MUC16 Enhances Pancreatic Cancer Cells Aggressiveness via α4β1 Integrin Complexes and FAK Signaling ». International Journal of Molecular Sciences 23, n^o 10 (13 mai 2022) : 5459. http://dx.doi.org/10.3390/ijms23105459.

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Elevated levels of Mucin-16 (MUC16) in conjunction with a high expression of truncated O-glycans is implicated in playing crucial roles in the malignancy of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms by which such aberrant glycoforms present on MUC16 itself promote an increased disease burden in PDAC are yet to be elucidated. This study demonstrates that the CRISPR/Cas9-mediated genetic deletion of MUC16 in PDAC cells decreases tumor cell migration. We found that MUC16 enhances tumor malignancy by activating the integrin-linked kinase and focal adhesion kinase (ILK/FAK)-signaling axis. These findings are especially noteworthy in truncated O-glycan (Tn and STn antigen)-expressing PDAC cells. Activation of these oncogenic-signaling pathways resulted in part from interactions between MUC16 and integrin complexes (α4β1), which showed a stronger association with aberrant glycoforms of MUC16. Using a monoclonal antibody to functionally hinder MUC16 significantly reduced the migratory cascades in our model. Together, these findings suggest that truncated O-glycan containing MUC16 exacerbates malignancy in PDAC by activating FAK signaling through specific interactions with α4 and β1 integrin complexes on cancer cell membranes. Targeting these aberrant glycoforms of MUC16 can aid in the development of a novel platform to study and treat metastatic pancreatic cancer.

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Ki, S. Y., H. Shin, Y. Lee, H. R. Bak, H. Yu, S. C. Kim, J. Lee, D. Kim, D. H. Ko et D. Kim. « AB0095 PRECLINICAL CHARACTERIZATION OF CJ-15314, A HIGHLY SELECTIVE JAK1 INHIBITOR, FOR THE TREATMENT OF AUTOIMMUNE DISEASES ». Annals of the Rheumatic Diseases 79, Suppl 1 (juin 2020) : 1347.2–1347. http://dx.doi.org/10.1136/annrheumdis-2020-eular.650.

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Background:Janus kinases (JAK1, JAK2, JAK3, and TYK2) play critical roles in mediating various cytokine signaling, and has been developed as a target for autoimmune diseases such as RA. Tofacitinib, oral Pan-JAK inhibitor, demonstrated efficacy in RA patients, but its widespread use is limited by safety issues. Baricitinib, JAK1/2 inhibitor, is also known to interfere with the hematopoiesis system, such as anemia and thrombocytopenia associated with suppression of JAK2 signals. Therefore, it is necessary to develop a new potent compound that selectively inhibits JAK1 over JAK2, 3Objectives:To identify the pharmacological characteristic based on efficacy of CJ-15314 as potent and selective JAK1 inhibitor for treatment of autoimmune disease.Methods:In vitro, cell-based, kinase panel, Kd value and human whole blood assay were performed to determine the inhibition potency and selectivity for JAK subfamily kinases. In vivo therapeutic potential was evaluated by RA model including rat Adjuvant-Induced Arthritis (AIA) and collagen-induced arthritic (CIA). To confirm the possibility of further expansion into the autoimmune disease, BioMAP® Diversity PLUS® Panel was performed by discoverX.Results:In vitro assay, CJ-15314 inhibited JAK kinase family in a concentration-dependent manner with IC50 values of 3.8 nM against JAK1, Selectivity for JAK1 over JAK2, 3 was approximately 18, 83 fold greater for CJ-15314. In 1mM ATP condition, CJ-15314 has been confirmed to have the highest JAK1 selectivity over competing drugs, under 1 mM ATP condition that reflects the physiological environment in the body. Similarly, Kd values has also confirmed the selectivity of JAK1, which is 10 fold higher than JAK2, 3. Accordingly, in human whole blood assays, CJ-15314 is 11 fold more potent against IL-6 induced pSTAT1 inhibition through JAK1 (IC50 value: 70 nM) than GM-CSF-induced pSTAT5 inhibition (JAK2) whereas baricitinib and filgotinib exhibited only 2 fold and 7 fold respectively.In vivo efficacy model, CJ-15314 inhibited disease severity scores in a dose dependent manner. In the rat AIA model, CJ-15314 at 30 mg/kg dose showed 95.3% decrease in arthritis activity score, 51.2% in figotinib at 30 mg/kg, 97.7% showed baricitinib at 10 mg/kg. CJ-15314 showed superior anti-arthritic efficacy than filgotinib. CJ-15314 also minimally affected anemia-related parameters but not bricitinib end of the 2-week treatment. In the rat CIA model, like 10 mg/kg of bricitinib, 30 mg/kg of CJ-15314 also has a similar effect, with a significant reduction in histopathological scores.In biomap diversity panel, CJ-15314 inhibited the expression of genes such as MCP-1, VCAM-1, IP-10, IL-8, IL-1, sTNF-α and HLA-DR confirming the possibility of expansion into other diseases beyond arthritis.Conclusion:CJ-15314 is a highly selective JAK1 inhibitor, demonstrates robust efficacy in RA animal model and is good candidate for further development for inflammatory diseases.* CJ-15314 is currently conducting a phase I trial in south Korea.References:[1]Clark JD et al. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014; 57(12):5023-38.[2]Burmester GR et al. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014; 10(2):77-88[3]Jean-Baptiste Telliez et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol., 2016; 11 (12):3442-3451Disclosure of Interests:so young Ki Employee of: CJ healthcare, hyunwoo shin Employee of: CJ healthcare, yelim lee Employee of: CJ healthcare, Hyoung rok Bak Employee of: CJ healthcare, hana yu Employee of: CJ healthcare, Seung Chan Kim Employee of: CJ healthcare, juhyun lee Employee of: CJ healthcare, donghyun kim Employee of: CJ healthcare, Dong-hyun Ko Employee of: CJ Healthcare, dongkyu kim Employee of: CJ healthcare

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Duan, Xinhang, Zhaoyu Wang, Yu Zhang, Han Li, Mei Yang, Hang Yin, Jing Cui et al. « Overexpression of a Thioredoxin-Protein-Encoding Gene, MsTRX, from Medicago sativa Enhances Salt Tolerance to Transgenic Tobacco ». Agronomy 12, n^o 6 (18 juin 2022) : 1467. http://dx.doi.org/10.3390/agronomy12061467.

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Thioredoxin (TRX) is a small molecule protein that participates in the redox process and plays a decisive role in various functions of plants. However, the role of TRX in Medicago sativa (alfalfa), a widely cultivated perennial herb of legume, is still poorly understood. Here, we isolated MsTRX from alfalfa and determined the characteristics in improving salt tolerance by assaying the phenotype and physiological changes and the expression of stress-response genes in transgenic tobacco. The expression of MsTRX was similar in alfalfa roots, leaves, and inflorescences, and was downregulated in response to cold, drought, and salt treatment. The overexpression of MsTRX in tobacco promoted the accumulation of soluble sugar (SS) and proline; enhanced the activity of peroxidase (POD); and induced the upregulation of beta-amylase 1 (BAM1), lipid-transfer protein 1 (LTP1), candidate signal molecules/sensor relay proteins (CBSX3), superoxide dismutase [Cu-Zn] (Cu/Zn-SOD), superoxide dismutase [Mn] (Mn-SOD), protein gamma response 1 (GR1), dehydrin DHN1-like (ERD10B), and serine/threonine-protein kinase (SnRK2), as well as the downregulation of phyB activation-tagged suppressor1 (BAS1) and serine/threonine-protein kinase that phosphorylates LHCII protein 7 (STN7) under salt stress. These results indicated that MsTRX improves salt tolerance via maintaining osmotic homeostasis, scavenging reactive oxygen species (ROS), and regulating the transcription of stress-response genes in plants. In our study, we provided a new understanding of how MsTRX improves salt stress in plants and how MsTRX can be included in future breeding programs to improve salt tolerance in alfalfa.

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Ruiz-Ortega, J. A., I. Lambarri, G. Bilbao, C. Miguelez, T. Morera-Herreras, E. Ruiz de Gopegui, B. Tijero et al. « ID 150 – STN neuron activity in patients carrying the R1441G mutation in the leucine-rich repeat kinase-2 (LRRK2) gene ». Clinical Neurophysiology 127, n^o 3 (mars 2016) : e80-e81. http://dx.doi.org/10.1016/j.clinph.2015.11.268.

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Li, Hui, Joseph Satriano, Joanna L. Thomas, Satoshi Miyamoto, Kumar Sharma, Núria M. Pastor-Soler, Kenneth R. Hallows et Prabhleen Singh. « Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease ». American Journal of Physiology-Renal Physiology 309, n^o 5 (1 septembre 2015) : F414—F428. http://dx.doi.org/10.1152/ajprenal.00463.2014.

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Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

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Cho, Jin Hyoung, Won Seok Ju, Sang Young Seo, Bo Hyun Kim, Ji-Su Kim, Jong-Geol Kim, Soon Ju Park et Young-Kug Choo. « The Potential Role of Human NME1 in Neuronal Differentiation of Porcine Mesenchymal Stem Cells : Application of NB-hNME1 as a Human NME1 Suppressor ». International Journal of Molecular Sciences 22, n^o 22 (11 novembre 2021) : 12194. http://dx.doi.org/10.3390/ijms222212194.

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This study aimed to investigate the effects of the human macrophage (MP) secretome in cellular xenograft rejection. The role of human nucleoside diphosphate kinase A (hNME1), from the secretome of MPs involved in the neuronal differentiation of miniature pig adipose tissue-derived mesenchymal stem cells (mp AD-MSCs), was evaluated by proteomic analysis. Herein, we first demonstrate that hNME1 strongly binds to porcine ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 (pST8SIA1), which is a ganglioside GD3 synthase. When hNME1 binds with pST8SIA1, it induces degradation of pST8SIA1 in mp AD-MSCs, thereby inhibiting the expression of ganglioside GD3 followed by decreased neuronal differentiation of mp AD-MSCs. Therefore, we produced nanobodies (NBs) named NB-hNME1 that bind to hNME1 specifically, and the inhibitory effect of NB-hNME1 was evaluated for blocking the binding between hNME1 and pST8SIA1. Consequently, NB-hNME1 effectively blocked the binding of hNME1 to pST8SIA1, thereby recovering the expression of ganglioside GD3 and neuronal differentiation of mp AD-MSCs. Our findings suggest that mp AD-MSCs could be a potential candidate for use as an additive, such as an immunosuppressant, in stem cell transplantation.

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Fukuyama, Kouji, et Motohiro Okada. « Age-Dependent and Sleep/Seizure-Induced Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy ». International Journal of Molecular Sciences 21, n^o 21 (30 octobre 2020) : 8142. http://dx.doi.org/10.3390/ijms21218142.

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The loss-of-function S284L-mutant α4 subunit of the nicotinic acetylcholine receptor (nAChR) is considered to contribute to the pathomechanism of autosomal dominant sleep-related hypermotor epilepsy (ADSHE); however, the age-dependent and sleep-related pathomechanisms of ADSHE remain to be clarified. To explore the age-dependent and sleep-induced pathomechanism of ADSHE, the present study determined the glutamatergic transmission abnormalities associated with α4β2-nAChR and the astroglial hemichannel in the hyperdirect and corticostriatal pathways of ADSHE model transgenic rats (S286L-TG) bearing the rat S286L-mutant Chrna4 gene corresponding to the human S284L-mutant CHRNA4 gene of ADSHE, using multiprobe microdialysis and capillary immunoblotting analyses. This study could not detect glutamatergic transmission in the corticostriatal pathway from the orbitofrontal cortex (OFC) to the striatum. Before ADSHE onset (four weeks of age), functional abnormalities of glutamatergic transmission compared to the wild-type in the cortical hyperdirect pathway, from OFC to the subthalamic nucleus (STN) in S286L-TG, could not be detected. Conversely, after ADSHE onset (eight weeks of age), glutamatergic transmission in the hyperdirect pathway of S286L-TG was enhanced compared to the wild-type. Notably, enhanced glutamatergic transmission of S286L-TG was revealed by hemichannel activation in the OFC. Expression of connexin43 (Cx43) in the OFC of S286L-TG was upregulated after ADSHE onset but was almost equal to the wild-type prior to ADSHE onset. Differences in the expression of phosphorylated protein kinase B (pAkt) before ADSHE onset between the wild-type and S286L-TG were not observed; however, after ADSHE onset, pAkt was upregulated in S286L-TG. Conversely, the expression of phosphorylated extracellular signal-regulated kinase (pErk) was already upregulated before ADSHE onset compared to the wild-type. Both before and after ADSHE onset, subchronic nicotine administration decreased and did not affect the both expression of Cx43 and pErk of respective wild-type and S286L-TG, whereas the pAkt expression of both the wild-type and S286L-TG was increased by nicotine. Cx43 expression in the plasma membrane of the primary cultured astrocytes of the wild-type was increased by elevation of the extracellular K+ level (higher than 10 mM), and the increase in Cx43 expression in the plasma membrane required pErk functions. These observations indicate that a combination of functional abnormalities, GABAergic disinhibition, and upregulated pErk induced by the loss-of-function S286L-mutant α4β2-nAChR contribute to the age-dependent and sleep-induced pathomechanism of ADSHE via the upregulation/hyperactivation of the Cx43 hemichannels.

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Yan, Xiaoying, Ran Zhao, Xiaorong Feng, Jingzhou Mu, Ying Li, Yue Chen, Chunmei Li et al. « Sialyltransferase7A promotes angiotensin II-induced cardiomyocyte hypertrophy via HIF-1α-TAK1 signalling pathway ». Cardiovascular Research 116, n^o 1 (11 mars 2019) : 114–26. http://dx.doi.org/10.1093/cvr/cvz064.

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Abstract Aims Sialylation is up-regulated during the development of cardiac hypertrophy. Sialyltransferase7A (Siat7A) mRNA is consistently over-expressed in the hypertrophic left ventricle of hypertensive rats independently of genetic background. The aims of this study were: (i) to detect the Siat7A protein levels and its roles in the pathological cardiomyocyte hypertrophy; (ii) to elucidate the effect of sialylation mediated by Siat7A on the transforming-growth-factor-β-activated kinase (TAK1) expression and activity in cardiomyocyte hypertrophy; and (iii) to clarify hypoxia-inducible factor 1 (HIF-1) expression was regulated by Siat7A and transactivated TAK1 expression in cardiomyocyte hypertrophy. Methods and results Siat7A protein level was increased in hypertrophic cardiomyocytes of human and rats subjected to chronic infusion of angiotensin II (ANG II). Delivery of adeno-associated viral (AAV9) bearing shRNA against rat Siat7A into the left ventricular wall inhibited ventricular hypertrophy. Cardiac-specific Siat7A overexpression via intravenous injection of an AAV9 vector encoding Siat7A under the cardiac troponin T (cTNT) promoter aggravated cardiac hypertrophy in ANG II-treated rats. In vitro, Siat7A knockdown inhibited the induction of Sialyl-Tn (sTn) antigen and cardiomyocyte hypertrophy stimulated by ANG II. Mechanistically, ANG II induced the activation of TAK1-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling in parallel to up-regulation of Siat7A in hypertrophic cardiomyocytes. Siat7A knockdown inhibited activation of TAK1-NF-κB pathway. Interestingly, HIF-1α expression was increased in cardiomyocytes stimulated by ANG II but decreased after Siat7A knockdown. HIF-1α knockdown efficiently decreased TAK1 expression. ChIP and luciferase assays showed that HIF-1α transactivated the TAK1 promoter region (nt −1285 to −1274 bp) in the cardiomyocytes following ANG II stimulus. Conclusion Siat7A was up-regulated in hypertrophic myocardium and promoted cardiomyocyte hypertrophy via activation of the HIF-1α-TAK1-NF-κB pathway.

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Park, Jae H., Stephen S. Chung, Young Rock Chung, Helen Won, Eunhee Kim, Alan Saven, Martha Wadleigh et al. « Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 24. http://dx.doi.org/10.1182/blood.v124.21.24.24.

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Abstract Background: Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a 30-40% relapse rate. For these patients (pts) and those intolerant to purine analogs, novel therapies are needed. The major finding that BRAFV600E mutations occur in 98% of HCL suggests BRAF as a promising therapeutic target. We therefore designed a phase II trial to (1) determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed/ refractory HCL and (2) identify biologic determinants of response and resistance to vemurafenib in HCL. Patients and Methods: Pts with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible pts received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Pts with partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional months. The primary endpoint of the study was overall response rate (ORR: CR + PR). Using a Simon’s mini-max two-stage design, if at least 4 of the 19 pts (≥20%) achieve ORR in the first stage, an additional 17 patients will be accrued to the second stage. If 11 or more pts achieve ORR out of the 36 pts, the study would be considered worthy of further investigation. Serial peripheral blood and/or BM samples were collected during the study for quantitative BRAF mutant allele burden, serum cytokine, multiparameter flow cytometry, and targeted next-generation sequencing analysis of a 350-gene panel to detect potential predictors of resistance and identify genes collaborating with BRAF mutations in HCL. Results: 22 pts have been enrolled and 20 pts received treatment. The median age was 61 years (range 44-77), and the median number of prior treatments was 3.5 (range 1-7). 20 pts are evaluable for toxicity and 17 patients for disease response with a median follow up of 10 months (range 2-19). The most common adverse events were rash (40%, Gr1-2), arthralgia (30%, Gr1-2), photosensitivity (20%, Gr1), and pruritis (15%, Gr1). Three pts developed squamous cell carcinoma (SCC), all of whom had previous history of SCC. All patients were able to complete the intended treatment (3 cycles: 11 pts, >3 cycles: 6 pts). All 17 evaluable pts achieved complete hematologic recovery with an overall response rate (ORR) of 100%. 6 pts achieved CR (4 MRD- and 2 MRD+) and 11 pts achieved PR with very minimal disease (Figure 1). Responses were rapid with reduction of circulating hairy cells within 24 hours and normalization of sCD25 within 2-3 weeks (Figure 2). This correlated with dephosphorylation of ERK at 1 month. Several additional inflammatory cytokines correlated with the leukemic cell burden identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R. Genetic analysis identified a median of 3 (range 0-5) somatic mutations co-existing with the BRAFV600E mutation in HCL including recurrent mutations in MLL2 and CREBBP (Figure 2). Several of these alterations were present as minor clones identifying a clonal architecture in HCL which was not previously appreciated. One pt was found to have de novo resistance to vemurafenib. Genetic analysis identified that this pt’s pretreatment HCL cells harbored a previously undescribed missense mutation in IRS1 (IRS1P1201S) in addition to BRAFV600E mutation. Given prior knowledge that IRS1 (Insulin Receptor Substrate 1) activates both MAP kinase and PI3K-AKT signaling, we compared the effects of expression of wildtype and mutant IRS1 cDNAs on signaling. This revealed robust activation of PI3K-AKT signaling induced by IRS1P1201S-mutant cells relative to wildtype. Conclusions: While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL. These data confirm the MAP kinase pathway as a rational promising therapeutic target in HCL and identify activation of signaling pathways parallel to the MAP kinase pathway as a first mechanism of RAF inhibitor resistance in a hematological malignancy. Subsequent studies will be required to prove that inhibition of B-raf may be the best initial therapy in HCL pts who require treatment. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Park: Genentech: Research Funding. Off Label Use: Vemurafenib in hairy cell leukemia. Rosen:Novartis: Consultancy.

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Tsurutani, Junji, Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura et al. « Abstract P1-12-08 : Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer : WJOG11418BTR NEWFLAME_TR ». Cancer Research 83, n^o 5_Supplement (1 mars 2023) : P1–12–08—P1–12–08. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-12-08.

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Abstract Background Previously, we reported the clinical outcomes of the combination of anti-PD-1 Ab, cyclin-dependent kinase 4/6 inhibitors, and endocrine therapy (ET) in patients with ER positive/HER2 negative advanced breast cancer in SABCS2020; biomarker analysis has been performed to provide insight into the hepatotoxicy frequently observed in the study. Methods Subjects received 240 mg nivolumab IV on days 1 and 15, 150 mg abemaciclib PO twice daily, and either 500 mg fulvestrant (FUL) on days 1, 15, 29, and every 4 weeks thereafter (FUL cohort) or 2.5 mg letrozole (LET) once daily (LET cohort). The primary endpoint was objective response rate and secondary endpoints included toxicity evaluated in the CTCAE along with an exploratory endpoint as related to the biomarker analysis. Archival tumor tissues were collected before study entry and blood and stool samples were collected at baseline and on cycle3 day1. Tumor tissues were subjected to IHC analysis and RNA sequencing followed by subtyping using NGS. High throughput cytokine analysis using ELISA-based assay were performed with serum samples and cell sorting analysis of PBMC was performed with FACS. Results From June 2019 to December 2019, 17 subjects were enrolled (FUL cohort [n = 12], LET cohort [n = 5]). The study was prematurely closed due to safety concerns such as hepatotoxicity and interstitial lung disease. AEs ≥ Grade 3 were observed in 91.7% and 100% of patients in the FUL and LET cohorts, respectively. The most frequent AEs ≥ Grade 3 were elevated liver function tests (LFT; FUL cohort: 50.0%, LET cohort: 60.0%). Serum cytokine analysis from the subjects with severe hepatotoxicity indicated cytokine storm with elevations of sCD30/TNFRSF8, IL-11, -34, Pentraxin-3, sTNF-R1, -R2, TSLP, which was supported by the findings of reduction of effector regulatory T cells in PBMC. IHC study in liver biopsy from three subjects with the toxicity revealed infiltration of CD8+ T cells and FOXP3+ T reg into the liver, suggesting the immune related liver injury upon the treatment with nivolumab and abemaciclib. HLA typing was performed in the 17 patients but no association between HLA type and ILD or hepatotoxicity were observed. Conclusions The frequent and severe immune related hepatotoxicity induced by the combination of anti-DD-1 and CDK 4/6 inhibitors might have been an immune-boosting therapy as suggested in the preclinical studies. This study was supported by the Ono Pharmaceutical Co., LTD. The registration number of the study is UMIN000036970. Citation Format: Junji Tsurutani, Jun Masuda, Norikazu Masuda, Yuko Tanabe, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K. Imamura, Sakiko Miura, Toshiko Yamochi, Kenichi Yoshimura, Toshimi Takano, Hidetaka Kawabata. Biomarker analysis of hepatotoxicity in a Phase II study of nivolumab, abemaciclib and endocrine therapy in patients with HR-positive, HER2-negative breast cancer: WJOG11418BTR NEWFLAME_TR [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-08.

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Park, Jae H., Stephen S. Chung, Young Rock Chung, Helen Won, Julie Teruya-Feldstein, Michael Berger, Talal T. Khawaja et al. « Phase II Trial Of The BRAF Inhibitor, Vemurafenib, In Patients With BRAF Mutant Relapsed Or Refractory Hairy Cell Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 2876. http://dx.doi.org/10.1182/blood.v122.21.2876.2876.

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Abstract Background Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a relapse rate of approximately 30%. For these patients (pts), novel therapies are needed. The recent major finding of the near universal and exclusive presence of BRAFV600E mutations in HCL has identified BRAF as a promising therapeutic target. BRAF inhibition in HCL may not only represent the first targeted therapeutic approach, but also a more effective strategy for treatment of HCL. Therefore, we have designed a phase II trial to determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed or refractory HCL. Patients and Methods Pts with HCL who are resistant to/intolerant of purine analogs, or who have achieved suboptimal response to purine analogs (i.e. relapse 22 years following completion of therapy, or who have ≥ 2 relapses) were enrolled to the trial. Pts must have an indication for treatment, as defined by ANC 21.0, HGB 210, PLT 2100K. Eligible pts received vemurafenib 960mg bid continuously in cycles of 4 weeks for 3 cycles. Bone marrow (BM) evaluations were performed after cycle 1 and 3. Pts with partial response (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional cycles at the discretion of treating physicians. Serial peripheral blood (PB) and/or BM samples were tested for BRAF IHC, quantitative BRAF mutant allele burden assessment by allele-specific qRT-PCR, serum cytokine analysis, detailed multiparameter flow cytometric analysis to identify the effect of vemurafenib on myeloid and lymphoid cell regeneration, and targeted next-generation sequencing analysis of a panel of 200 genes known to be mutated in cancer and/or associated with response to MAP kinase pathway inhibitors to detect potential predictors of response to vemurafenib and identify genes collaborating with BRAF mutations in HCL pathogenesis. Results To date, 9 pts have been enrolled and 8 pts received the treatment. The median age was 62 years (range 49-77 years), and the median number of treatments prior to the study was 3.5 (range 1-7), including 2 pts with splenectomy. 5 pts are evaluable for toxicity and disease response. The most common adverse events were rash (Grade 2: 4 pts), photosensitivity (Grade 1-3: 3 pts), arthralgia (Grade 2-3: 3 pts), hand-foot syndrome (Grade 2: 1 pt), febrile neutropenia (Grade 3: 1 pt) and tumor lysis syndrome (Grade 3: 1 pt). One pt developed new squamous cell carcinoma while on therapy and successfully underwent complete resection. 4 pts required dose reductions to 480mg bid due to side effects of arthralgia, symptomatic hand-foot syndrome and febrile neutropenia, but all were able to complete all intended treatment. All 5 pts achieved complete hematologic recovery. 2 pts achieved marrow CR (1 MRD positive and the other MRD negative), and 3 pts achieved marrow PR with very minimal disease. Responses were rapid and evident by PB flow cytometric analysis 24 hours after the initial dose (Figure 1). Plasma levels of sCD25 normalized within 2-3 weeks, and this correlated with a rapid decrease of BRAF+ hairy cells and dephosphorylation of ERK after one cycle (Figure 2). Several additional inflammatory cytokines correlated closely with the burden of leukemic cells identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R. Continued improvement in response rates was noted when assessed at the end of cycle 1 and 3, as documented by paired PB and BM multiparametric flow cytometric analysis. 2 pts with PR after cycle 1 converted to CR after cycle 3, and, in the remaining 3 pts who maintained PR, the amount of disease burden further decreased from cycle 1 to cycle 3. Genetic analysis is ongoing and has identified mutations in MLL2 and CREBBP, genes previously described to be mutated in other B cell malignancies but not previously described in HCL. Conclusions While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL and confirm the MAP kinase pathway as a rational promising therapeutic target in HCL. However, the optimal dose and duration of the drug in HCL remain unknown, and further studies are warranted. Enrollment is ongoing to this study, and updated clinical and genetic analysis data will be presented. Disclosures: No relevant conflicts of interest to declare.

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Szczepanek, Joanna, Joanna Laskowska, Agata Labedzka, Jan Styczynski et Andrzej Tretyn. « Genetic Mechanisms Of Cytarabine, Etoposide and Daunorubicin Resistance In Pediatric Acute Leukemias ». Blood 122, n^o 21 (15 novembre 2013) : 4938. http://dx.doi.org/10.1182/blood.v122.21.4938.4938.

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Abstract Introduction Drug resistance is a major problem in chemotherapy of leukemia. Several mechanisms of this phenomenon have been identified, but the underlying genomic changes are still poorly understood. Lack of drug sensitivity arises from a complex range of molecular events, which ultimately result in the blasts escaping death. Analysis of the gene expression profiles of cancer cells in correlation with in vitro cytotoxicity assay may define mechanisms of sensitivity and resistance to specific drugs. OBJECTIVE: To define and compare whole-genome responses to cytarabine (Ara-C), etoposide (VP16) and daunorubicin (DNR) in pediatric patients diagnosed with acute leukemias, and to explain in vitro chemoresistance phenotype of leukemic blasts. Methods In order to determine the ex vivo drug resistance profile, MTT cytotoxicity assay was performed on mononuclear cells obtained from 51 patients with ALL and 16 patients with AML. Gene expression profiles were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were performed during the correlation analysis for identified probe sets. Verification of the relative expression level of genes (EGR1, GATA2, RUFY3, LDHA, DUSP2, BIN2, ICAM3, TTC28) was carried out by RT-qPCR in the study group and in an independent group of 53 patients. Results Genetic expression profiles were identified, including those appropriate for ALL and AML: 181 and 106 genes for Ara-C, 274 and 314 for VP16, 146 and 495 for the DNR. For each of the drugs, a characteristic group of genes or processes that are responsible for the lack of sensitivity, were identified: (1) for Ara-C: overexpression of genes responsible for removing the drug from the cells, as well as changes in the nucleic acid metabolic process, especially transcription from RNA polymerase II promoter (eg. ZBTB16, FOSB, NFATC1, ZNF518B, PHF20L1 and RUFY); (2) for VP16: changes in expression level of genes involved in the regulation of mRNA transcription and DNA metabolism genes, including those controlling replication as well as those belonging to the double helix damage repair enzymes and genes participating in post-transcriptional mRNA splicing (eg. TOP2B, CSNK1E, BRIP1, ATR, MSH3 and MSH6); (3) for DNR: differentiated expression of factors involved in the replication and transcription processes, increased expression of kinases and intensification of the DNA repair processes (eg. ATF2, GATA2, TOX, RUNX3, MNDA, ST18, TFDP1, NFE2, SOX11 and PAX5). For each profile several common genes, such as: AGAP1, PRKCH, RAB31, BCL2A1, GCA, HLA-DRA, HLA-DPA1, IL8, RGS10, CEBPD, CLEC2, ANXA1, PLEK, S100A8, SLC, CXCL2, SOX, BTG, DEFA4 and TPD52, were identified. Pathway and functional gene ontology analysis showed that several features, independent of the initial type of leukemia cells and pattern of resistance include: overexpression of chemokines and hydrolases, increase in the expression of genes responsible for the maintenance of chromatin architecture, overexpression of anti-apoptotic genes, decrease in expression level of genes that promote apoptosis, decrease in gene expression of Wnt signaling pathway, down regulation of the expression of transcription factors, changes in the expression level of genes associated with the activation of B and T lymphocytes, differences in expression of genes responsible for the cell surface receptor linked signal transduction and intracellular signaling cascade. Conclusions This analysis showed that the mechanism of response to drugs is significantly genetically determined. Predictive sets of marker genes and functional groups for simultaneous assessment of the sensitivity to these 3 drugs, were identified. Many of these changes converge and ultimately lead to avoidance of apoptosis and further over-proliferation of cancer cells. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes in pediatric acute leukemias. This could also suggest that targeting these pathways as potential pharmacogenetics and therapeutic candidates may be useful for improving treatment outcomes. Acknowledgments: This study was supported by Grant from the National Science Centre No. DEC-2011/03/D/NZ5/05749. Disclosures: No relevant conflicts of interest to declare.

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Longoni, Fiamma Paolo, et Michel Goldschmidt-Clermont. « Thylakoid Protein Phosphorylation in Chloroplasts ». Plant and Cell Physiology, 26 mars 2021. http://dx.doi.org/10.1093/pcp/pcab043.

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Abstract Because of their abundance and extensive phosphorylation, numerous thylakoid proteins stand out amongst the phosphoproteins of plants and algae. In particular, subunits of light-harvesting complex II (LHCII) and of photosystem II (PSII) are dynamically phosphorylated and dephosphorylated in response to light conditions and metabolic demands. These phosphorylations are controlled by evolutionarily conserved thylakoid protein kinases and counteracting protein phosphatases, which have distinct but partially overlapping substrate specificities. The best characterized are the kinases STATE TRANSITION 7 (STN7/STT7) and STATE TRANSITION 8 (STN8), and the antagonistic phosphatases PROTEIN PHOSPHATASE 1/THYLAKOID-ASSOCIATED PHOSPHATASE 38 (PPH1/TAP38) and PHOTOSYSTEM II CORE PHOSPHATASE (PBCP). The phosphorylation of LHCII is mainly governed by STN7 and PPH1/TAP38 in plants. LHCII phosphorylation is essential for state transitions, a regulatory feedback mechanism that controls the allocation of this antenna to either PSII or PSI, and thus maintains the redox balance of the electron transfer chain. Phosphorylation of several core subunits of PSII, regulated mainly by STN8 and PBCP, correlates with changes in thylakoid architecture, the repair cycle of PSII after photodamage as well as regulation of light harvesting and of alternative routes of photosynthetic electron transfer. Other kinases, such as the PLASTID CASEIN KINASE II (pCKII), also intervene in thylakoid protein phosphorylation and take part in the chloroplast kinase network. While some features of thylakoid phosphorylation were conserved through the evolution of photosynthetic eukaryotes, others have diverged in different lineages possibly as a result of their adaptation to varied environments.

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Wunder, Tobias, Wenteng Xu, Qiuping Liu, Gerhard Wanner, Dario Leister et Mathias Pribil. « The major thylakoid protein kinases STN7 and STN8 revisited : effects of altered STN8 levels and regulatory specificities of the STN kinases ». Frontiers in Plant Science 4 (2013). http://dx.doi.org/10.3389/fpls.2013.00417.

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