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Zeitschriftenartikel zum Thema "Dark kinase"
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Soleymani, Saber, Nathan Gravel, Liang-Chin Huang, Wayland Yeung, Elika Bozorgi, Nathaniel G. Bendzunas, Krzysztof J. Kochut und Natarajan Kannan. „Dark kinase annotation, mining, and visualization using the Protein Kinase Ontology“. PeerJ 11 (05.12.2023): e16087. http://dx.doi.org/10.7717/peerj.16087.
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The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human and machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns and drug interactions. Furthermore, we have developed a completely new browser from the ground up to render the knowledge graph visible and interactive on the web. We have enriched ProKinO with new classes and relationships that capture information on kinase ligand binding sites, expression patterns, and functional features. These additions extend ProKinO’s capabilities as a discovery tool, enabling it to uncover novel insights about understudied members of the protein kinase family. We next demonstrate the application of ProKinO. Specifically, through graph mining and aggregate SPARQL queries, we identify the p21-activated protein kinase 5 (PAK5) as one of the most frequently mutated dark kinases in human cancers with abnormal expression in multiple cancers, including a previously unappreciated role in acute myeloid leukemia. We have identified recurrent oncogenic mutations in the PAK5 activation loop predicted to alter substrate binding and phosphorylation. Additionally, we have identified common ligand/drug binding residues in PAK family kinases, underscoring ProKinO’s potential application in drug discovery. The updated ontology browser and the addition of a web component, ProtVista, which enables interactive mining of kinase sequence annotations in 3D structures and Alphafold models, provide a valuable resource for the signaling community. The updated ProKinO database is accessible at https://prokino.uga.edu.
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Needham, Elise J., Benjamin L. Parker, Timur Burykin, David E. James und Sean J. Humphrey. „Illuminating the dark phosphoproteome“. Science Signaling 12, Nr. 565 (22.01.2019): eaau8645. http://dx.doi.org/10.1126/scisignal.aau8645.
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Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology. However, current biochemical and bioinformatic approaches have only identified kinases for less than 5% of the phosphoproteome, and functional assignments of phosphosites are almost negligible. Notably, our understanding of the relationship between kinases and their substrates follows a power law distribution, with almost 90% of phosphorylation sites currently assigned to the top 20% of kinases. In addition, more than 150 kinases do not have a single known substrate. Despite a small group of kinases dominating biomedical research, the number of substrates assigned to a kinase does not correlate with disease relevance as determined by pathogenic human mutation prevalence and mouse model phenotypes. Improving our understanding of the substrates targeted by all kinases and functionally annotating the phosphoproteome will be broadly beneficial. Advances in phosphoproteomics technologies, combined with functional screening approaches, should make it feasible to illuminate the connectivity and functionality of the entire phosphoproteome, providing enormous opportunities for discovering new biology, therapeutic targets, and possibly diagnostics.
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Sawyers, Charles L. „Will Kinase Inhibitors Have a Dark Side?“ New England Journal of Medicine 355, Nr. 3 (20.07.2006): 313–15. http://dx.doi.org/10.1056/nejmcibr062354.
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Berginski, Matthew E., Nienke Moret, Changchang Liu, Dennis Goldfarb, Peter K. Sorger und Shawn M. Gomez. „The Dark Kinase Knowledgebase: an online compendium of knowledge and experimental results of understudied kinases“. Nucleic Acids Research 49, Nr. D1 (20.10.2020): D529—D535. http://dx.doi.org/10.1093/nar/gkaa853.
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Abstract Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH’s Illuminating the Druggable Genome (IDG) Program, the DKK is focused on data and knowledge generation for 162 poorly studied or ‘dark’ kinases. Types of data provided through the DKK include parallel reaction monitoring (PRM) peptides for quantitative proteomics, protein interactions, NanoBRET reagents, and kinase-specific compounds. Higher-level data is similarly being generated and consolidated such as tissue gene expression profiles and, longer-term, functional relationships derived through perturbation studies. Associated web tools that help investigators interrogate both internal and external data are also provided through the site. As an evolving resource, the DKK seeks to continually support and enhance knowledge on these potentially high-impact druggable targets.
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Southekal, Siddesh, Nitish Kumar Mishra und Chittibabu Guda. „Pan-Cancer Analysis of Human Kinome Gene Expression and Promoter DNA Methylation Identifies Dark Kinase Biomarkers in Multiple Cancers“. Cancers 13, Nr. 6 (10.03.2021): 1189. http://dx.doi.org/10.3390/cancers13061189.
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Kinases are a group of intracellular signaling molecules that play critical roles in various biological processes. Even though kinases comprise one of the most well-known therapeutic targets, many have been understudied and therefore warrant further investigation. DNA methylation is one of the key epigenetic regulators that modulate gene expression. In this study, the human kinome’s DNA methylation and gene expression patterns were analyzed using the level-3 TCGA data for 32 cancers. Unsupervised clustering based on kinome data revealed the grouping of cancers based on their organ level and tissue type. We further observed significant differences in overall kinase methylation levels (hyper- and hypomethylation) between the tumor and adjacent normal samples from the same tissue. Methylation expression quantitative trait loci (meQTL) analysis using kinase gene expression with the corresponding methylated probes revealed a highly significant and mostly negative association (~92%) within 1.5 kb from the transcription start site (TSS). Several understudied (dark) kinases (PKMYT1, PNCK, BRSK2, ERN2, STK31, STK32A, and MAPK4) were also identified with a significant role in patient survival. This study leverages results from multi-omics data to identify potential kinase markers of prognostic and diagnostic importance and further our understanding of kinases in cancer.
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Cozza, G., F. Meggio und S. Moro. „The Dark Side of Protein Kinase CK2 Inhibition“. Current Medicinal Chemistry 18, Nr. 19 (01.06.2011): 2867–84. http://dx.doi.org/10.2174/092986711796150423.
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Anandakrishnan, Manju, Karen E. Ross, Chuming Chen, Vijay Shanker, Julie Cowart und Cathy H. Wu. „KSFinder—a knowledge graph model for link prediction of novel phosphorylated substrates of kinases“. PeerJ 11 (06.10.2023): e16164. http://dx.doi.org/10.7717/peerj.16164.
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Background Aberrant protein kinase regulation leading to abnormal substrate phosphorylation is associated with several human diseases. Despite the promise of therapies targeting kinases, many human kinases remain understudied. Most existing computational tools predicting phosphorylation cover less than 50% of known human kinases. They utilize local feature selection based on protein sequences, motifs, domains, structures, and/or functions, and do not consider the heterogeneous relationships of the proteins. In this work, we present KSFinder, a tool that predicts kinase-substrate links by capturing the inherent association of proteins in a network comprising 85% of the known human kinases. We also postulate the potential role of two understudied kinases based on their substrate predictions from KSFinder. Methods KSFinder learns the semantic relationships in a phosphoproteome knowledge graph using a knowledge graph embedding algorithm and represents the nodes in low-dimensional vectors. A multilayer perceptron (MLP) classifier is trained to discern kinase-substrate links using the embedded vectors. KSFinder uses a strategic negative generation approach that eliminates biases in entity representation and combines data from experimentally validated non-interacting protein pairs, proteins from different subcellular locations, and random sampling. We assess KSFinder’s generalization capability on four different datasets and compare its performance with other state-of-the-art prediction models. We employ KSFinder to predict substrates of 68 “dark” kinases considered understudied by the Illuminating the Druggable Genome program and use our text-mining tool, RLIMS-P along with manual curation, to search for literature evidence for the predictions. In a case study, we performed functional enrichment analysis for two dark kinases - HIPK3 and CAMKK1 using their predicted substrates. Results KSFinder shows improved performance over other kinase-substrate prediction models and generalized prediction ability on different datasets. We identified literature evidence for 17 novel predictions involving an understudied kinase. All of these 17 predictions had a probability score ≥0.7 (nine at >0.9, six at 0.8–0.9, and two at 0.7–0.8). The evaluation of 93,593 negative predictions (probability ≤0.3) identified four false negatives. The top enriched biological processes of HIPK3 substrates relate to the regulation of extracellular matrix and epigenetic gene expression, while CAMKK1 substrates include lipid storage regulation and glucose homeostasis. Conclusions KSFinder outperforms the current kinase-substrate prediction tools with higher kinase coverage. The strategically developed negatives provide a superior generalization ability for KSFinder. We predicted substrates of 432 kinases, 68 of which are understudied, and hypothesized the potential functions of two dark kinases using their predicted substrates.
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Salcedo, Mariah V., Nathan Gravel, Abbas Keshavarzi, Liang-Chin Huang, Krzysztof J. Kochut und Natarajan Kannan. „Predicting protein and pathway associations for understudied dark kinases using pattern-constrained knowledge graph embedding“. PeerJ 11 (18.10.2023): e15815. http://dx.doi.org/10.7717/peerj.15815.
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The 534 protein kinases encoded in the human genome constitute a large druggable class of proteins that include both well-studied and understudied “dark” members. Accurate prediction of dark kinase functions is a major bioinformatics challenge. Here, we employ a graph mining approach that uses the evolutionary and functional context encoded in knowledge graphs (KGs) to predict protein and pathway associations for understudied kinases. We propose a new scalable graph embedding approach, RegPattern2Vec, which employs regular pattern constrained random walks to sample diverse aspects of node context within a KG flexibly. RegPattern2Vec learns functional representations of kinases, interacting partners, post-translational modifications, pathways, cellular localization, and chemical interactions from a kinase-centric KG that integrates and conceptualizes data from curated heterogeneous data resources. By contextualizing information relevant to prediction, RegPattern2Vec improves accuracy and efficiency in comparison to other random walk-based graph embedding approaches. We show that the predictions produced by our model overlap with pathway enrichment data produced using experimentally validated Protein-Protein Interaction (PPI) data from both publicly available databases and experimental datasets not used in training. Our model also has the advantage of using the collected random walks as biological context to interpret the predicted protein-pathway associations. We provide high-confidence pathway predictions for 34 dark kinases and present three case studies in which analysis of meta-paths associated with the prediction enables biological interpretation. Overall, RegPattern2Vec efficiently samples multiple node types for link prediction on biological knowledge graphs and the predicted associations between understudied kinases, pseudokinases, and known pathways serve as a conceptual starting point for hypothesis generation and testing.
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Weiss, Ellen. „Shedding light on dark adaptation“. Biochemist 42, Nr. 5 (09.10.2020): 44–50. http://dx.doi.org/10.1042/bio20200067.
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The retina is famous for its ability to operate under a broad range of light intensities. This is partly due to the presence of two types of photoreceptor cells, rods and cones. Rods are used mostly for dim light vision, and cones are used for bright light and colour vision. These cells are also able to adapt to a broad range of light intensities using light- and dark-adaptation mechanisms. Dark adaptation is used by the vertebrate retina to increase its visual sensitivity when moving from a brightly lit environment to a dark environment. The brighter the surrounding light, the longer it takes for the retina to adapt to the dark. Most retina biologists have studied dark adaptation by exposing animals to a 90% bleach, meaning that 90% of the light-sensing proteins in these photoreceptor cells have been activated, followed by transfer of these animals to a dark room and analysis of their light sensitivity using electrophysiological methods. In this report, we introduce the basic elements of the visual system and describe how the system might operate during dark adaptation. We also introduce a novel role for cAMP-mediated phosphorylation of G protein-coupled receptor kinase 1 (GRK1), a major kinase in visual signalling.
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Jiang, Wen, Eric Jaehnig und Bing Zhang. „Abstract 2023: CoPheeMap: a co-regulation map of 30,000 phosphosite illuminates the dark cancer phosphoproteome“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 2023. http://dx.doi.org/10.1158/1538-7445.am2023-2023.
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Abstract Mass spectrometry-based phosphoproteomics enables proteome-wide analysis of protein phosphorylation in biological samples. As a prime example, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has performed phosphoproteomic profiling for 1,191 tumors spanning 11 cancer types, generating quantitative data on 77,442 phosphosites. Despite the impressive data generation power, only less than 5% of these phosphosites have been associated with a regulatory kinase or biological function, and 90% of these annotated phosphosites were associated with 20% well-studied kinases. The “dark” phosphoproteome greatly limits our ability to gain functional insights into cancer signaling. Previous research has shown that co-regulation is a strong indicator of functional association. Here we leveraged machine learning and the vast amount of CPTAC data to build a co-regulation map of phosphosites to facilitate functional interpretation of phosphoproteomics findings. Based on a ground-truth dataset including 98,402 pairs of phosphosites known to be regulated by the same kinase (positives) and 1,317,273 pairs by kinases from distant kinase families (negatives), we developed an Extreme Gradient Boosting (XGBoost) classifier to distinguish the positive and negative pairs using CPTAC phosphoproteomic data, protein-protein interaction data, and phosphopeptide sequences. Applying the trained classifier to 3 billion phosphosite pairs identified 2,569,519 (0.08%) with high probability of co-regulation, i.e., 400 times more likely to connect positive pairs than negative pairs in an independent ground-truth dataset. These pairs constituted a co-regulation map of 30,499 unique phosphosites, called CoPheeMap.To demonstrate the utility of CoPheeMap, we integrated its network embedding features, embedding features from a kinase network, together with Position-Specific Scoring Matrices scores and site-kinase abundance associations to develop a XGBoost model to predict kinase substrate associations (KSAs). The resulted model CoPheeKSA showed superior performance with an AUROC of 0.97 and identified 12,000 high-quality novel KSAs involving 7,908 phosphosites. In another application, CoPheeMap based information propagation (CoPheeProp) assigned 5,000 phosphosites to different signaling pathways with high specificity, increasing existing knowledge by 9-fold. Applying CoPheeMap and the derived tools to CPTAC and other cancer phosphoproteomics datasets revealed regulatory and functional information for previously unannotated sites showing strong associations with somatic mutations and cancer phenotypes, leading to actionable mechanistic and therapeutic insights. Together, CoPheeMap, CoPheeKSA and CoPheeProp provide a systematic framework to illuminate the dark phosphoproteome and have broad applications ranging from basic cancer biology research to clinical investigations. Citation Format: Wen Jiang, Eric Jaehnig, Bing Zhang. CoPheeMap: a co-regulation map of 30,000 phosphosite illuminates the dark cancer phosphoproteome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2023.
Dissertationen zum Thema "Dark kinase"
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Lin, Yao. „Control of DAPK-1 degradation“. Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4189.
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DAPK-1 is calcium-calmodulin regulated protein kinase involved in multiple cellular pathways including apoptosis, autophagy, cell survival and motility. The cytokine TNF-α has been reported to induce the degradation of DAPK-1. Here I identified the protease cathepsin B as a novel binding partner of DAPK-1 that protects DAPK-1 from TNF-α induced degradation. Using deletion mutants of DAPK-1, I mapped the cathepsin B binding domain on DAPK-1 to amino acids 836-947. Overexpression of this mini-protein DAPK-1(836-947) facilitated degradation of full-length DAPK-1 and apoptosis induced by TNFR-1. Moreover, siRNA mediated knock-down of DAPK-1 enhanced TNF-α induced apoptosis, confirming the role of DAPK-1 as a survival factor in the TNF-α signalling pathway. In addition, a splice variant of DAPK-1, which I have called s-DAPK-1, was discovered. s-DAPK-1 shares part of DAPK-1’s ankyrin repeats region and cytoskeletal binding domain, and possesses an unique tail region, which contains a cleavage site at its first two amino acids. Unlike DAPK-1, s-DAPK-1 does not contribute to apoptosis induced by high level of MEK/ERK signalling, but it does mimic DAPK-1’s function to induce membrane blebbing. The proteolytically processed form of s-DAPK-1 is more active in the induction of membrane blebbing, which may be due to its higher stability compared to that of full-length s-DAPK-1, suggesting that the tail region can control s-DAPK-1 stability and activity. Co-transfection of s-DAPK-1 and DAPK-1 leads to reduction in DAPK-1 expression level, suggesting a role for s-DAPK-1 to regulate DAPK-1 stability. The kinase domain of DAPK-1 is the region required for s-DAPK-1 to promote DAPK-1 degradation. Surprisingly, s-DAPK-1 does not bind directly to DAPK-1, suggesting that the interaction is indirect and mediated by as yet unidentified accessory proteins. Finally, the experiments with proteasome and lysosome inhibitors indicated that s-DAPK-1 induces DAPK-1 degradation via both lysosome and proteasome pathways.
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Lorén, Christina. „Investigating the function of the Receptor Tyrosine Kinase ALK during Drosophila melanogaster development“. Doctoral thesis, Umeå universitet, Umeå centrum för molekylär patogenes (UCMP), 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-411.
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The Drosophila melanogaster gene Anaplastic Lymphoma Kinase (DAlk) is homologous to mammalian Alk, which is a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). In humans the t(2;5) translocation involving the Alk locus encodes an active form of Alk that is the causative agent in Non-Hodgkin’s Lymphoma (Morris et al., 1994). Alk has also been associated with other cancers such as inflammatory myofibroblastic tumours (IMTs). The physiological function of the Alk RTK has not been described in any system until very recently, and is still not defined in vertebrates. The molecular similarity between Drosophila Alk and mammalian Alk suggested that mutation of Alk in flies may affect similar functional and developmental processes, and thus lead to some understanding of Alk function in vivo. By employing an EMS mutagenesis screen we were able to obtain loss-of-function mutants in the Drosophila DAlk gene. Eleven independent DAlk mutants were identified and characterized. DAlk is normally expressed in the developing gut and in the CNS. DAlk mutant animals have a lethal phenotype and die at late embryonic stages or as 1st instar larva. In DAlk mutant embryos there is a complete failure in the development of the midgut whereas the CNS appears normal. The midgut consists of visceral musculature that is syncytial and is formed by fusion of multiple myoblasts. This is a dynamic process where two types of myoblasts, i.e. fusion-competent-myoblasts and founder-cells that function as seeds for muscle formation, fuse. In DAlk homozygous embryos there is no founder cell specification, which explains the failure of midgut formation in these embryos. Recently a novel secreted molecule Jelly Belly (Jeb) was identified. Jeb is expressed in the tissue neighbouring the DAlk expressing cells of the developing visceral mesoderm. Jeb mutant embryos show a phenotype that is similar to that of DAlk mutant embryos. We have been able to show that Jeb is the ligand for DAlk in the developing visceral mesoderm and that Jeb binding stimulates a DAlk driven ERK signaling pathway. This leads to the expression of Dumbfounded (duf)/kin of Irregular chiasm-C (kirre), a founder-cell specific immunoglobulin that has an important role in myoblast aggregation and fusion. The functional Drosophila midgut is made up of the visceral muscle that encircles the endodermal tube. This tube formation includes migration of cells originating in the anterior and posterior parts of the embryo, first along the anterior-posterior axis using the visceral mesoderm as a template, then dorsally and ventrally. In DAlk mutant embryos there is no visceral muscle fusion and both the visceral mesoderm and the endoderm fail to undergo dorsal-ventral migration.
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Yang, Lei. „Structural studies on human dihydroxyacetone kinase (DAK) and the carbohydrate-binding domain of Streptococcus pneumoniae NanA“. Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4506.
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A number of dihydroxyacetone kinases (DAK) have been described that can utilize either ATP (in animals, plants and some bacteria) or phosphoenolpyruvate (PEP) (in most bacteria) as the energy source to convert dihydroxyacetone (Dha) to dihydroxyacetone phosphate (DhaP), which plays critical roles in many metabolic pathways. It has also been described that Homo sapiens DAK is able to regulate the innate immune system via its interaction with Melanoma differentiation-associated protein 5 (MDA5), which is recognized as an RNA sensor during virus infection. These findings make H. sapiens DAK a very noteworthy research target due to its multiple functions in many fields. Therefore, structural studies of DAK from H. sapiens are presented. The initial structure of the wild type (WT) H. sapiens DAK was determined to 2.5Å resolution and solved by molecular replacement. The structure forms a homodimer and four dimers were shown to be present in each asymmetric unit. However, within each monomer, most regions of the C-terminal domain were disordered, and therefore in order to improve structure quality, multiple site-directed mutagenesis was used. The mutated protein was then crystallized and the structure was determined to 1.4Å. The N-terminal Dha binding domain consists of two α/β regions and the C-terminal ATP binding domain is comprised of eight anti-parallel α-helices, which forms a deep pocket and is filled with a phospholipid molecule. In addition, the structures of mutated DAK in complex with ATP analogues and Dha are also described in the current study. The second part of the project concerned sialidases, which are glycoside hydrolases that specifically hydrolyse terminal sialic acid from various glycans. Streptococcus pneumoniae is one of the most common pathogenic bacteria of humans, and is reported to encode three sialidases that act as virulence factors in bacterial colonization and infection. One of these sialidases, NanA, was reported to be present in all clinical strains and plays a vital role during the bacterial infection. Consequently, the structure of N-terminal Carbohydrate-binding module (CBM) domain of NanA has been determined to 1.8Å, and reveals a β-sandwich fold. The apo form of NanA-CBM is present as a dimer in the asymmetric unit, whereas a monomer was detected when it is bound to sialic acid or its derivatives. Structural comparisons between NanA-CBM and other structures of the CBM40 family were also performed. The substrate binding sites of NanA-CBM forms a cavity that is able to accommodate the substrates. A potential molecular binding site located beside the sialic acid binding site was revealed, and is occupied by the side chain of a lysine from a symmetry- related molecule. Heteronuclear single quantum coherence (HSQC) NMR spectroscopy and fluorescent-based thermal shift assays were also carried out to further characterise the protein. The current results reveal the structure of both DAK from H. sapiens and NanA-CBM from S. pneumoniae, which may contribute to a better understanding towards cell metabolism and bacterial colonization.
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Vaultier, Marie-Noëlle. „Etude de la perception et de la transduction du signal froid chez Arabidopsis thaliana : Implication des voies de signalisation lipidique“. Paris 6, 2006. http://www.theses.fr/2006PA066223.
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Keitz, Fabienne Dominique von [Verfasser], Christian [Akademischer Betreuer] Peschel und Gisela [Akademischer Betreuer] Keller. „Die Koexpression von Aurora A Kinase und EGFR ist prognostisch für Patienten mit Plattenepithelkarzinomen des Kopf- Hals- Bereichs und stellt eine Zielstruktur für die Therapie dar / Fabienne Dominique von Keitz. Gutachter: Gisela Keller ; Christian Peschel. Betreuer: Christian Peschel“. München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1058434632/34.
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Kongs, Veronica Louise. „Graduate band conducting recital : lesson plans and theoretical/historical analysis of literature“. Manhattan, Kan. : Kansas State University, 2007. http://hdl.handle.net/2097/365.
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Furlong, Pierce James. „Aspects of ancient Near Eastern chronology (c. 1600-700 BC)“. Melbourne, 2007. http://repository.unimelb.edu.au/10187/2096.
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The chronology of the Late Bronze and Early Iron Age Near East is currently a topic of intense scholarly debate. The conventional/orthodox chronology for this period has been assembled over the past one-two centuries using information from King-lists, royal annals and administrative documents, primarily those from the Great Kingdoms of Egypt, Assyria and Babylonia. This major enterprise has resulted in what can best be described as an extremely complex but little understood jigsaw puzzle composed of a multiplicity of loosely connected data. I argue in my thesis that this conventional chronology is fundamentally wrong, and that Egyptian New Kingdom (Memphite) dates should be lowered by 200 years to match historical actuality. This chronological adjustment is achieved in two stages: first, the removal of precisely 85 years of absolute Assyrian chronology from between the reigns of Shalmaneser II and Ashur-dan II; and second, the downward displacement of Egyptian Memphite dates relative to LBA Assyrian chronology by a further 115 years. Moreover, I rely upon Kuhnian epistemology to structure this alternate chronology so as to make it methodologically superior to the conventional chronology in terms of historical accuracy, precision, consistency and testability.
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Weraduwage, Sarathi. „Harnessing the anabolic properties of dark respiration to enhance sink activity at elevated CO2 using Arabidopsis thaliana L. with partially-suppressed mitochondrial pyruvate dehydrogenase kinase“. Thesis, 2013. http://hdl.handle.net/10214/6759.
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Sink limitations in plants reduce the potential for photosynthesis and yield, particularly under conditions that favour enhanced source activity such as elevated CO2 (EC). Dark respiration, considered catabolic, has rarely been exploited to enhance sink activity in plants. Arabidopsis thaliana L. lines with partially-suppressed mitochondrial pyruvate dehydrogenase (mtPDH) kinase (mtPDHK), a negative post-translational regulator of the mtPDH complex, was shown previously to have both elevated mtPDH complex activity and increased seed weight and oil content at ambient CO2 (AC), suggesting an enhancement of sink activity. The mtPDH links glycolysis with the tricarboxylic acid (TCA) cycle. It was hypothesized that Arabidopsis having suppressed mtPDHK will display their greatest plant productivity at EC through a combined enhancement of source and sink activities. Control and transgenic Arabidopsis having either constitutive or seed-specific expression of antisense mtPDHK were grown at either AC or EC. Expression of mtPDHK and mtPDH complex activity in rosette leaves and reproductive tissues were measured, which required the development of an assay to quantify mtPDH activity. Vegetative and reproductive growth over time, seed oil
parameters, and leaf net C exchange were also quantified. A parabolic relationship was found between mtPDHK expression and mtPDH activity, reflecting a role for mtPDH in balancing photosynthetic and respiratory processes. A number of growth and seed oil parameters were improved in transgenic lines, particularly at EC; many of these parameters showed a
significant linear or quadratic correlation with mtPDHK expression and mtPDH activity. The proportion of very long chain fatty acids was increased in transgenic lines. Leaf net C exchange was enhanced at AC and EC, and particularly in lines showing repression of mtPDHK. The greatest enhancement in total seed and oil productivity was found for the constitutive lines 104 and 31 at EC (up to 2.8 times). These two lines exhibited a significant increase in inflorescence size, an increase in leaf water use efficiency, the lowest rate of mtPDH complex inactivation by ATP, and an intermediary enhancement of mtPDH complex
activity in seeds. Thus, it is concluded that the mtPDH plays a key role in regulating sink and source activities in plants.Natural Sciences and Engineering Research Council (NSERC) through the Green Crop Networks Research Network; Ontario Graduate Scholarship; Syngenta Graduate Scholarship; Ball Farm Services and Agrico Canada Ltd. Scholarship; Mrs. Fred Ball Scholarship; Arthur D. Latornell Scholarship; Hoskins Scholarship; Robb Travel Grant; Registrars and the Deans Scholarship and travel awards and bursaries from the University of Guelph, and the Ontario Agricultural College.
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Widau, Ryan Cole. „Protein phosphatase 2A (PP2A) holoenzymes regulate death associated protein kinase (DAPK) in ceramide-induced anoikis“. Thesis, 2010. http://hdl.handle.net/1805/2131.
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Indiana University-Purdue University Indianapolis (IUPUI)Modulation of sphingolipid-induced apoptosis is a potential mechanism to enhance the effectiveness of chemotherapeutic drugs. Ceramide is a pleiotropic, sphingolipid produced by cells in response to inflammatory cytokines, chemotherapeutic drugs and ionizing radiation. Ceramide is a potent activator of protein phosphatases, including protein phosphatase 2A (PP2A) leading to dephosphorylation of substrates important in regulating mitochondrial dysfunction and apoptosis. Previous studies demonstrated that death associated protein kinase (DAPK) plays a role in ceramide-induced apoptosis via an unknown mechanism. The tumor suppressor DAPK is a calcium/calmodulin regulated serine/threonine kinase with an important role in regulating cytoskeletal dynamics. Auto-phosphorylation within the calmodulin-binding domain at serine308 inhibits DAPK catalytic activity. Dephosphorylation of serine308 by a hitherto unknown phosphatase enhances kinase activity and proteasomal mediated degradation of DAPK. In these studies, using a tandem affinity purification procedure coupled to LC-MS/MS, we have identified two holoenzyme forms of PP2A as DAPK interacting proteins. These phosphatase holoenzymes dephosphorylate DAPK at Serine308 in vitro and in vivo resulting in enhanced kinase activity of DAPK. The enzymatic activity of PP2A also negatively regulates DAPK protein levels by enhancing proteasomal-mediated degradation of the kinase, as a means to attenuate prolonged kinase activation. These studies also demonstrate that ceramide causes a caspase-independent cell detachment in HeLa cells, a human cervical carcinoma cell line. Subsequent to detachment, these cells underwent caspase-dependent apoptosis due to lack of adhesion, termed anoikis. Overexpression of wild type DAPK induced cell rounding and detachment similar to cells treated with ceramide; however, this effect was not observed following expression of a phosphorylation mutant, S308E DAPK. Finally, the endogenous interaction of DAPK and PP2A was determined to be required for ceramide-induced cell detachment and anoikis. Together these studies have provided exciting and essential new data regarding the mechanisms of cell adhesion and anoikis. These results define a novel cellular pathway initiated by ceramide-mediated activation of PP2A and DAPK to regulate inside-out signaling and promote anoikis.
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Tzeng, Ruei-Ying, und 曾瑞瑩. „Study of death-associated protein kinase (DAPK) regulation by EBV in B lymphocytes“. Thesis, 2008. http://ndltd.ncl.edu.tw/handle/24477145512452718471.
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碩士國立陽明大學
醫學生物技術暨檢驗學系暨研究所
96
Epstein-Barr virus (EBV) belongs to human γ-herpes virus and is associated with many human lymphoproliferative malignancies such as Burkitt’s and Hodgkin’s lymphomas. Primary B cells can be immortalized by EBV to become lymphoblastoid cell lines (LCLs) in vitro. Previous researches indicate that many cellular gene expressions are altered in EBV-infected B cells. In our previous study, we demonstrated that a gene, death-associated protein kinase (DAPK), was upregulated in time after EBV infected cells and LCLs, but it had no enzymatic activity in LCLs by in vitro kinase assay. DAPK is a Ca2+/calmodulin-regulated Ser/Thr kinase that mediates cell death. The function of DAPK is silenced under normal growth conditions, but rapidly activated in response to appropriate apoptotic signals or oxidative stress. Yet how DAPK is regulated by EBV infection and its role in EBV infected cells are merely understood. Here, we found the EBV latent membrane protein (LMP1) may be responsible for upregulation of DAPK expression in LCLs and HeLa cells. Then we showed that EBV induced DAPK expression may be through the NFκB signaling. Further we found that less cells died in LCLs with low DAPK expression (sh-DAPK LCLs) than control LCLs (sh-luc LCLs) after UV irradiation or H2O2 treatment. It implied that DAPK still has the ability to mediate cell death in LCLs, and we proposed this function may be inhibited by EBV in the normal environment. Taken together, our data suggest that LMP1 may increase DAPK expression in LCLs and HeLa cells, and these increases of expression may be through the NFκB signaling. The endogenous DAPK still can regulate cell death after stress signals, but how the inhibitory mechanisms suppress DAPK activation in normal condition remains to be investigated.
Bücher zum Thema "Dark kinase"
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Gemmell, David. Dark prince. New York: Ballantine Books, 1991.
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Gemmell, David. Dark prince. New York: Ballantine Books, 1993.
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3
Gemmell, David. Dark prince. London: Century, 1991.
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4
Inc, Mada Design, Hrsg. The Dark Fortress. New York: Scholastic, 2005.
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5
Duhig, Ian. The speed of dark. London: Picador, 2007.
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6
Shreeve, Nicholas. Dark legacy: The fortunes of Begam Samru. Calcutta: Rupa & Co., 1998.
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7
Koen, Karleen. Dark angels: A novel. New York: Crown, 2006.
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8
Koen, Karleen. Dark angels: A novel. New York: Random House Large Print, 2006.
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Indonesia, Persekutuan Gereja-Gereja di. Dari Kinasih ke Mamasa: Sebuah catatan perjalanan pelayanan PGI masa bakti 2004-2009. [Jakarta]: Persekutuan Gereja-Gereja di Indonesia, 2009.
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10
John, Judith. A dark history : Tudors: Murder, adultery, incest, witchcraft, wars, religious persecution, piracy. New York: Metro Books, 2014.
Den vollen Inhalt der Quelle findenBuchteile zum Thema "Dark kinase"
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Vener, A. V., P. J. M. van Kan, A. Gal, I. Ohad und B. Andersson. „Reversible Activation of LHCII Kinase by Transient Low pH Treatment of Thylakoids in the Dark“. In Photosynthesis: from Light to Biosphere, 1545–48. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-009-0173-5_363.
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Peters, H. „Magen-Darm-Trakt“. In Die Ultraschalluntersuchung des Kindes, 269–88. Berlin, Heidelberg: Springer Berlin Heidelberg, 1997. http://dx.doi.org/10.1007/978-3-642-59139-6_11.
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Légeret, Corinne, und Margarete Bolten. „Materialien zur Diagnostik bei funktionellen Magen-Darm-Störungen“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 183–91. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_8.
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Bolten, Margarete, und Corinne Légeret. „Materialien zur interdisziplinären Behandlung bei funktionellen Magen-Darm-Störungen“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 193–228. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_9.
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Légeret, Corinne, und Margarete Bolten. „Pathogenese funktioneller gastrointestinaler Störungen“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 51–83. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_5.
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Légeret, Corinne, und Margarete Bolten. „Klinische Symptomatik und Klassifikation funktioneller gastrointestinaler Störungen im Kindes- und Jugendalter“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 33–50. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_4.
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Bolten, Margarete, und Corinne Légeret. „Therapieansätze bei funktionellen gastrointestinalen Störungen“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 127–80. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_7.
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Légeret, Corinne, und Margarete Bolten. „Diagnostik und Differenzialdiagnostik bei funktionellen Darmstörungen“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 87–125. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_6.
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Bolten, Margarete. „Die Sauberkeitsentwicklung im Kindesalter“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 25–32. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_3.
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Bolten, Margarete. „Psychosoziale Aspekte der Nahrungsaufnahme, Verdauung und Ausscheidung“. In Funktionelle Magen-Darm-Störungen im Kindes- und Jugendalter, 13–24. Berlin, Heidelberg: Springer Berlin Heidelberg, 2022. http://dx.doi.org/10.1007/978-3-662-64253-5_2.
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Essegian, Derek J., Rimpi Khurana, Vasileios Stathias, Valery Chavez, Jaime R. Merchan und Stephan Schürer. „Abstract 5103: The dark cancer kinome - untapped opportunities for the development of novel drugs“. In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-5103.
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Essegian, Derek J., Rimpi Khurana, Vasileios Stathias, Valery Chavez, Jaime R. Merchan und Stephan Schürer. „Abstract 5103: The dark cancer kinome - untapped opportunities for the development of novel drugs“. In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-5103.
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Mejtoft, Thomas, Erik Frängsmyr, Ulrik Söderström und Ole Norberg. „Deceptive Design: Cookie Consent and Manipulative Patterns“. In Digital Support from Crisis to Progressive Change. University of Maribor Press, 2021. http://dx.doi.org/10.18690/978-961-286-485-9.29.
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As a larger proportion of our lives moves onto the web, so does important and valuable information. This has led to an increase in different kinds of manipulative patterns (dark patterns) in web design with the sole purpose of being deceptive and tricking users. This paper discusses the comprehensive suite of deceptive design patterns on Internet services where the users are expected to comply with the use of cookies. This was done by analyzing 50 different home cooking recipe websites, regarding their appliance to GDPR and how they use different dark patterns in their design. Even though legislation tries to move the choices from the website to the user, it is clear that by using deceptive design patterns it is possible to “bypass” the legislation and trick the user into making a favorable choice for the owners behind the website. The results show that out of the websites that were GDPR approved, a majority still use two types of deceptive design patterns - misdirection and sneak into basket.
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Xu, Shou-long, und Shu-liang Zou. „Video Monitoring System Availability in Radiation Accident Condition“. In 2016 24th International Conference on Nuclear Engineering. American Society of Mechanical Engineers, 2016. http://dx.doi.org/10.1115/icone24-60848.
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Study of availability in radiation environment is presented for video monitoring system. Testing experiment has been completed by seven kinds of Image sensor module which includes three kinds of digital image sensor module and four kinds of analog image sensor module. Radiation accident condition was simulated by γ-ray ionizing radiation environment where the dose rate at 16.63Gy/h 20.20Gy/h and 58.30Gy/h. Availability has been studied by analyzing real time monitoring image quality parameters captured in γ-ray exposure environment. The primary image quality parameters include average gray level of the dark image and synthetic brightness of the color image. The most suitable image sensor module has been selected by image quality parameters for comparison before and after irradiation. Experimental results show that, digital camera has minimum background noise. The radiation resistance of CMOS image sensors is better than CCD image sensors. Therefore, digital video monitoring system with CMOS image sensor has the best image quality parameters and slightest effect in γ-ray ionizing radiation environment where the dose rate is less than 58.30Gy/h. Meanwhile, adequate light could reduce noise interference reduced by γ-ray for all types of video monitoring system. However, digital signal processing integrated circuit board has been destroyed when the accumulated dose reach to 88.40Gy, but the CMOS image sensor integrated circuit board has normal working parameters. As a conclusion, digital video monitoring system with CMOS image sensor could be used for real-time monitoring in radiation accident condition, but the digital signal processing integrated circuit board needs to be hardened by radiation hardened technology.
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Furuya, Yoshiyuki, Saburo Matsuoka und Takayuki Abe. „Frequency Effects on Gigacycle Fatigue Properties of High-Strength Steels“. In ASME/JSME 2004 Pressure Vessels and Piping Conference. ASMEDC, 2004. http://dx.doi.org/10.1115/pvp2004-2986.
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This report will reveal a series of fatigue test results for high-strength steels at 100 Hz and 20 kHz and discuss frequency effects on gigacycle fatigue properties. The 20 kHz fatigue testing machine is an effective tool to conduct gigacycle fatigue tests in a reasonable term, while frequency effects have to be carefully investigated before applying the machine. The fatigue tests were conducted for two kinds of high-strength steels, that were a low-alloy steel and a spring steel. These fatigue test results showed that the frequency effects were negligible even at 20 kHz in case of fish-eye fracture. The fatigue properties in the fish-eye fracture region showed a good agreement between the 100 Hz and 20 kHz tests. Besides, ODAs (Optically Dark Areas) were also observed on the fracture surface even in 20 kHz tests and no difference was found in the ODA sizes between the 100 Hz and 20 kHz tests. These results meant that the 20 kHz tests could provide us appropriate results at least in the fish-eye fracture region. Therefore, the 20 kHz tests were applicable on the evaluation of gigacycle fatigue properties in high-strength steels.
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Ciolan, Laura elena. „DIGIKIDS: TECHNOLOGY MEDIATED DEVELOPMENT, BEYOND FEAR AND STEREOTYPES“. In eLSE 2012. Editura Universitara, 2012. http://dx.doi.org/10.12753/2066-026x-12-075.
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The social and pedagogical discourse about ”digital natives”, Millennials, or ”digikids” is not so new anymore, but as the case with many serious, even dramatic changes, a whole range of stereotypes and prejudices developed concerning this new generation, seriously affecting he quality of interaction with adults in general, and the quality of educational interaction in particular. We will try in this paper to look the the learning characteristics of the new generation of kids, as well as on their consequences in designing learning experiences. Quality of the new generations is not intrinsic, nor by default jeopardized by their immersion in technologically rich environments. Beyond fear and stereotypes, we have to see how the encounter with this new generation could bring the most educational benefits, in a world that reconcile their lived experiences and our (adults) care and concerns. Recent research shows that as educationalists we have to take this reality as seriously as possible, as being the potentially new starting point of a learning revolution. There is a whole spectacle and still a challenge to see how small kinds, target group of early education (below 7 years old) interact and develop behavioral approaches in technologically reach environments. The ”light side” of technologies impacting on kids development at early ages cannot be neglected, and this is not to assume that, necessarily, is automatically balanced by a ”dark side”... Our paper tries to offer a realistic and balanced view on how early education should try to address this new generation, in order to stimulate and significantly contribute to their development.
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Chi Hsu, Ying, I. Wen Yen und Meng-Cong Zheng. „Knowledge Visualization of Earthquake: Impact of Design Format on Readers' Perception and Understanding“. In 14th International Conference on Applied Human Factors and Ergonomics (AHFE 2023). AHFE International, 2023. http://dx.doi.org/10.54941/ahfe1003221.
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To strengthen the seismic intensity and differentiate adaptations to earthquakes in Taiwan, the Central Weather Bureau of the Ministry of Transportation and Communications subdivided the original seismic intensity of 5 Strong and 6 Violent earthquakes of the Seismic Intensity Scale into 5 Lower and 5 Upper, 6 Lower and 6 Upper respectively in 2020.First, we collected 28 infographics from domestic and overseas governmental and private institutions and stock image websites using earthquake intensity as the keyword. Three researchers with design backgrounds classified the infographics into three kinds of types for experimentation: 1) a single-color gradient (semi-circular car dashboard) with an illustration of a cabinet or a house; 2) a 3D geometry (horseshoe type) with illustrations of people and scenes inside and outside the house; 3) a traditional table (horizontal type) with an illustration of a house. The text descriptions of the three infographics were the same. Sixteen respondents (10 of whom had 5-year design background) read through the three infographics sequentially and did a 7-Point Likert Scale Questionnaire. The questions included design form (format, logic, and clarity of information), perception and understanding (distinguishing seismic hazards, perceiving intensity differences, and rapid understanding), risk perception, and personal preference. Finally, semi-structured interviews were to gain a deeper understanding of what factors influence readers' priorities in reading the earthquake intensity infographics.This study found that: 1) a semi-circle speed gauge with one color gradient using light to dark orange had the highest perception and understanding score (mean = 5.19); 2) 3D geometry with horseshoe shape with illustrations and information richness had the highest design form score (mean = 5.13) and highest personal preference ranking; 3) formatting tables with stereotypical image and only one house illustration could not determine the difference had the lowest design form score (mean = 4.65) and lowest perception and understanding score (mean = 4.93) and lowest personal preference ranking. The lowest scores for design form (mean = 4.65), perception and understanding (mean = 4.93), and personal preference were the lowest. In addition, 80% of the respondents were concerned about earthquakes and prepared for them, but more than half would not evacuate quickly during an earthquake. Suggestions for the future are that the earthquake infographics could use color gradients and 3D geometry so that the public can differentiate the danger in different intensity scales.
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Vanegas Luna, Laura. „El juego como re-significador de la circunstancia y la ciudad“. In Seminario Internacional de Investigación en Urbanismo. Bogotá: Universidad Piloto de Colombia, 2022. http://dx.doi.org/10.5821/siiu.10461.
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Play, understood as a social activity practiced by humans, takes place in its own kind of place: the playspace. This text finds itself on the premise that play allows players to understand and use an environment in new and unforeseen ways, assigning new meanings and interpretations to the city and said environment. Thus, this text supports itself on the study of games performed in public spaces, a hide-and-seek session and conversations held with Pokémon Go users. Taking these studies into account, unique and different kinds of living and experiencing a place during a play session can be identified. In this way, unexpected and unplanned visions of the city and inhabited environments are acknowledged due to the performance of play.
Keywords: playspace, play in the city, public space, cities revisited
Topic: Public space and urban project in the contemporary city Entendiendo el juego como una actividad social y desarrollada en su propio tipo de espacio, el espacio de juego, esta propuesta parte entonces de la premisa de que el juego es una actividad que permite reinterpretar y usar de maneras no programadas el entorno en el que se ubica, con lo cual el individuo puede significar y resignificar la ciudad y su entorno inmediato. Así, este trabajo toma un ejercicio de observación de juegos en espacio público, una sesión de juego del escondite y entrevistas a jugadores de Pokémon Go, para dar cuenta de una particularidad en las formas de vivir y experimentar un lugar durante el desarrollo de un juego, por medio de lo cual se adquiere una visión no prevista, ni proyectada, de la ciudad y espacios habitados en la vida cotidiana.
Palabras clave: espacio de juego, juego en la ciudad, espacio público, resignificación de la ciudad
Bloque temático: Espacio público y proyecto urbano en la metrópolis contemporánea
Berichte der Organisationen zum Thema "Dark kinase"
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Lers, Amnon, und Gan Susheng. Study of the regulatory mechanism involved in dark-induced Postharvest leaf senescence. United States Department of Agriculture, Januar 2009. http://dx.doi.org/10.32747/2009.7591734.bard.
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Postharvest leaf senescence contributes to quality losses in flowers and leafy vegetables. The general goal of this research project was to investigate the regulatory mechanisms involved in dark-induced leaf senescence. The regulatory system involved in senescence induction and control is highly complex and possibly involves a network of senescence promoting pathways responsible for activation of the senescence-associated genes. Pathways involving different internal signals and environmental factors may have distinctive importance in different leaf senescence systems. Darkness is known to have a role in enhancement of postharvest leaf senescence and for getting an insight into its regulatory mechanism/s we have applied molecular genetics and functional genomics approaches. The original objectives were: 1. Identification of dark-induced SAGs in Arabidopsis using enhancer/promoter trap lines and microarray approaches; 2. Molecular and functional characterization of the identified genes by analyzing their expression and examining the phenotypes in related knockout mutant plants; 3. Initial studies of promoter sequences for selected early dark-induced SAGs. Since genomic studies of senescence, with emphasis on dark-induced senescence, were early-on published which included information on potential regulatory genes we decided to use this new information. This is instead of using the uncharacterized enhancer/promoter trap lines as originally planned. We have also focused on specific relevant genes identified in the two laboratories. Based on the available genomic analyses of leaf senescence 10 candidate genes hypothesized to have a regulatory role in dark-induced senescence were subjected to both expression as well as functional analyses. For most of these genes senescence-specific regulation was confirmed, however, functional analyses using knock-out mutants indicated no consequence to senescence progression. The transcription factor WARK75 was found to be specifically expressed during natural and dark-induced leaf senescence. Functional analysis demonstrated that in detached leaves senescence under darkness was significantly delayed while no phenotypic consequences could be observed on growth and development, including no effect on natural leaf senescence,. Thus, WARKY75 is suggested to have a role in dark-induced senescence, but not in natural senescence. Another regulatory gene identified to have a role in senescence is MKK9 encoding for a Mitogen-Activated Protein Kinase Kinase 9 which is upregulated during senescence in harvested leaves as well as in naturally senescing leaves. MKK9 can specifically phosphorylate another kinase, MPK6. Both knockouts of MKK9 and MPK6 displayed a significantly senescence delay in harvested leaves and possibly function as a phosphorelay that regulates senescence. To our knowledge, this is the first report that clearly demonstrates the involvement of a MAP kinase pathway in senescence. This research not only revealed a new signal transduction pathway, but more important provided significant insights into the regulatory mechanisms underlying senescence in harvested leaves. In an additional line of research we have employed the promoter of the senescence-induced BFN1 gene as a handle for identifying components of the regulatory mechanism. This gene was shown to be activated during darkinduced senescence of detached leaves, as well as natural senescence. This was shown by following protein accumulation and promoter activity which demonstrated that this promoter is activated during dark-induced senescence. Analysis of the promoter established that, at least some of the regulatory sequences reside in an 80 bps long fragment of the promoter. Overall, progress was made in identification of components with a role in dark-induced senescence in this project. Further studies should be done in order to better understand the function of these components and develop approaches for modulating the progress of senescence in crop plants for the benefit of agriculture.
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Chamovitz, Daniel, und Albrecht Von Arnim. Translational regulation and light signal transduction in plants: the link between eIF3 and the COP9 signalosome. United States Department of Agriculture, November 2006. http://dx.doi.org/10.32747/2006.7696515.bard.
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The COP9 signalosome (CSN) is an eight-subunit protein complex that is highly conserved among eukaryotes. Genetic analysis of the signalosome in the plant model species Arabidopsis thaliana has shown that the signalosome is a repressor of light dependent seedling development as mutant Arabidopsis seedlings that lack this complex develop in complete darkness as if exposed to light. These mutant plants die following the seedling stage, even when exposed to light, indicating that the COP9 signalosome also has a central role in the regulation of normal photomorphogenic development. The biochemical mode of action of the signalosome and its position in eukaryotic cell signaling pathways is a matter of controversy and ongoing investigation, and recent results place the CSN at the juncture of kinase signaling pathways and ubiquitin-mediated protein degradation. We have shown that one of the many CSN functions may relate to the regulation of translation through the interaction of the CSN with its related complex, eukaryotic initiation factor (eIF3). While we have established a physical connection between eIF3 subunits and CSN subunits, the physiological and developmental significance of this interaction is still unknown. In an effort to understand the biochemical activity of the signalosome, and its role in regulating translation, we originally proposed to dissect the contribution of "h" subunit of eIF3 (eIF3h) along the following specific aims: (i) Isolation and phenotypic characterization of an Arabidopsis loss-of-function allele for eIF3h from insertional mutagenesis libraries; (ii) Creation of designed gain and loss of function alleles for eIF3h on the basis of its nucleocytoplasmic distribution and its yeast-two-hybrid interactions with other eIF3 and signalosome partner proteins; (iii) Determining the contribution of eIF3h and its interaction with the signalosome by expressing specific mutants of eIF3h in the eIF3h- loss-of function background. During the course of the research, these goals were modified to include examining the genetic interaction between csn and eif3h mutations. More importantly, we extended our effort toward the genetic analysis of mutations in the eIF3e subunit, which also interacts with the CSN. Through the course of this research program we have made several critical scientific discoveries, all concerned with the apparent diametrically opposed roles of eIF3h and eIF3e. We showed that: 1) While eIF3e is essential for growth and development, eIF3h is not essential for growth or basal translation; 2) While eIF3e has a negative role in translational regulation, eIF3h is positively required for efficient translation of transcripts with complex 5' UTR sequences; 3) Over-accumulation of eIF3e and loss-of-function of eIF3h both lead to cop phenotypes in dark-grown seedlings. These results were published in one publication (Kim et al., Plant Cell 2004) and in a second manuscript currently in revision for Embo J. Are results have led to a paradigm shift in translation research – eIF3 is now viewed in all systems as a dynamic entity that contains regulatory subuits that affect translational efficiency. In the long-term agronomic outlook, the proposed research has implications that may be far reaching. Many important plant processes, including developmental and physiological responses to light, abiotic stress, photosynthate, and hormones operate in part by modulating protein translation [23, 24, 40, 75]. Translational regulation is slowly coming of age as a mechanism for regulating foreign gene expression in plants, beginning with translational enhancers [84, 85] and more recently, coordinating the expression of multiple transgenes using internal ribosome entry sites. Our contribution to understanding the molecular mode of action of a protein complex as fundamental as eIF3 is likely to lead to advances that will be applicable in the foreseeable future.