Zeitschriftenartikel: „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.

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Lee, Horim. „Mitogen-Activated Protein Kinase Kinase 3 Is Required for Regulation during Dark-Light Transition“. Molecules and Cells 38, Nr. 7 (17.06.2015): 651–56. http://dx.doi.org/10.14348/molcells.2015.0055.

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Deznabi, Iman, Busra Arabaci, Mehmet Koyutürk und Oznur Tastan. „DeepKinZero: zero-shot learning for predicting kinase–phosphosite associations involving understudied kinases“. Bioinformatics 36, Nr. 12 (11.02.2020): 3652–61. http://dx.doi.org/10.1093/bioinformatics/btaa013.

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Abstract Motivation Protein phosphorylation is a key regulator of protein function in signal transduction pathways. Kinases are the enzymes that catalyze the phosphorylation of other proteins in a target-specific manner. The dysregulation of phosphorylation is associated with many diseases including cancer. Although the advances in phosphoproteomics enable the identification of phosphosites at the proteome level, most of the phosphoproteome is still in the dark: more than 95% of the reported human phosphosites have no known kinases. Determining which kinase is responsible for phosphorylating a site remains an experimental challenge. Existing computational methods require several examples of known targets of a kinase to make accurate kinase-specific predictions, yet for a large body of kinases, only a few or no target sites are reported. Results We present DeepKinZero, the first zero-shot learning approach to predict the kinase acting on a phosphosite for kinases with no known phosphosite information. DeepKinZero transfers knowledge from kinases with many known target phosphosites to those kinases with no known sites through a zero-shot learning model. The kinase-specific positional amino acid preferences are learned using a bidirectional recurrent neural network. We show that DeepKinZero achieves significant improvement in accuracy for kinases with no known phosphosites in comparison to the baseline model and other methods available. By expanding our knowledge on understudied kinases, DeepKinZero can help to chart the phosphoproteome atlas. Availability and implementation The source codes are available at https://github.com/Tastanlab/DeepKinZero. Supplementary information Supplementary data are available at Bioinformatics online.

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Hao, Yuhan, Haijiao Wang, Shenglong Qiao, Linna Leng und Xuelu Wang. „Histone deacetylase HDA6 enhances brassinosteroid signaling by inhibiting the BIN2 kinase“. Proceedings of the National Academy of Sciences 113, Nr. 37 (25.08.2016): 10418–23. http://dx.doi.org/10.1073/pnas.1521363113.

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Glycogen synthase kinase 3 (GSK3)-like kinases play important roles in brassinosteroid (BR), abscisic acid, and auxin signaling to regulate many aspects of plant development and stress responses. The Arabidopsis thaliana GSK3-like kinase BR-INSENSITIVE 2 (BIN2) acts as a key negative regulator in the BR signaling pathway, but the mechanisms regulating BIN2 function remain unclear. Here we report that the histone deacetylase HDA6 can interact with and deacetylate BIN2 to repress its kinase activity. The hda6 mutant showed a BR-repressed phenotype in the dark and was less sensitive to BR biosynthesis inhibitors. Genetic analysis indicated that HDA6 regulates BR signaling through BIN2. Furthermore, we identified K189 of BIN2 as an acetylated site, which can be deacetylated by HDA6 to influence BIN2 activity. Glucose can affect the acetylation level of BIN2 in plants, indicating a connection to cellular energy status. These findings provide significant insights into the regulation of GSK3-like kinases in plant growth and development.

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Wykosky, Jill, Akitake Mukasa, Frank Furnari und Webster K. Cavenee. „Escape from targeted inhibition: The dark side of kinase inhibitor therapy“. Cell Cycle 9, Nr. 9 (Mai 2010): 1661–62. http://dx.doi.org/10.4161/cc.9.9.11592.

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Liu, Jia, Xuan Wang, Yuanqin Zhu, Huilin Deng, Xin Huang, Pallavi Jayavanth, Ying Xiao, Jianlin Wu und Rui Jiao. „Theabrownin from Dark Tea Ameliorates Insulin Resistance via Attenuating Oxidative Stress and Modulating IRS-1/PI3K/Akt Pathway in HepG2 Cells“. Nutrients 15, Nr. 18 (05.09.2023): 3862. http://dx.doi.org/10.3390/nu15183862.

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Dark tea has great potential in regulating glycolipid metabolism, and theabrownin (TB) is considered to be the characteristic and bioactive constituent of dark tea. This study evaluated the ability of TB1 (fermented for 7 days) and TB2 (fermented for 14 days) isolated from dark tea to reverse insulin resistance (IR) in HepG2 cells. The results indicated that TB significantly ameliorated oxidative stress by improving mitochondrial function. In addition, TB improved glycogen synthesis and glucose consumption, and inhibited gluconeogenesis and fatty acid synthesis, by regulating GSK3β (Glycogen synthase kinase 3β), G6Pase (Glucose-6-phosphatase), GCK (Glucokinase), PEPCK1 (Phosphoenolpyruvate carboxy kinase 1), SREBP-1C (sterol regulatory element-binding protein 1C), FASN (fatty acid synthase), and ACC (Acetyl-CoA carboxylase). Additionally, the results of Western blot and real-time PCR experiments demonstrated that TB modulated glucolipid metabolism through the IRS-1 (Insulin receptor substrate 1)/PI3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B) signaling pathway. Treatment with the PI3K inhibitor demonstrated a favorable correlation between PI3K activation and TB action on glycolipid metabolism. Notably, we observed that TB2 had a greater effect on improving insulin resistance compared with TB1, which, due to its prolonged fermentation time, increased the degree of oxidative polymerization of TB.

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Chu, Brian, Che-Hsiung Liu, Sukanya Sengupta, Amit Gupta, Padinjat Raghu und Roger C. Hardie. „Common mechanisms regulating dark noise and quantum bump amplification in Drosophila photoreceptors“. Journal of Neurophysiology 109, Nr. 8 (15.04.2013): 2044–55. http://dx.doi.org/10.1152/jn.00001.2013.

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Absolute visual thresholds are limited by “dark noise,” which in Drosophila photoreceptors is dominated by brief (∼10 ms), small (∼2 pA) inward current events, occurring at ∼2/s, believed to reflect spontaneous G protein activations. These dark events were increased in rate and amplitude by a point mutation in myosin III (NINAC), which disrupts its interaction with the scaffolding protein, INAD. This phenotype mimics that previously described in null mutants of ninaC (no inactivation no afterpotential; encoding myosin III) and an associated protein, retinophilin ( rtp). Dark noise was similarly increased in heterozygote mutants of diacylglycerol kinase ( rdgA/+). Dark noise in ninaC, rtp, and rdgA/+ mutants was greatly suppressed by mutations of the Gq α-subunit ( Gα q) and the major light-sensitive channel ( trp) but not rhodopsin. ninaC, rtp, and rdgA/+ mutations also all facilitated residual light responses in Gα q and PLC hypomorphs. Raising cytosolic Ca2+ in the submicromolar range increased dark noise, facilitated activation of transient receptor potential (TRP) channels by exogenous agonist, and again facilitated light responses in Gα q hypomorphs. Our results indicate that RTP, NINAC, INAD, and diacylglycerol kinase, together with a Ca2+-dependent threshold, share common roles in suppressing dark noise and regulating quantum bump generation; consequently, most spontaneous G protein activations fail to generate dark events under normal conditions. By contrast, quantum bump generation is reliable but delayed until sufficient G proteins and PLC are activated to overcome threshold, thereby ensuring generation of full-size bumps with high quantum efficiency.

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Węgrzyn, Anna, Małgorzata Krysiak, Anna Kulik, Katarzyna B. Gieczewska und 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, Nr. 9 (20.04.2022): 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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SENIN, Ivan I., Kevin R. DEAN, Aminullah A. ZARGAROV, Muhammad AKHTAR und Pavel P. PHILIPPOV. „Recoverin inhibits the phosphorylation of dark-adapted rhodopsin more than it does that of bleached rhodopsin: a possible mechanism through which rhodopsin kinase is prevented from participation in a side reaction“. Biochemical Journal 321, Nr. 2 (15.01.1997): 551–56. http://dx.doi.org/10.1042/bj3210551.

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In its resting state rhodopsin kinase is present in an inactive form and is activated after interaction with light-activated rhodopsin (Rho*). The activated rhodopsin kinase then phosphorylates Rho* but is also able to catalyse the phosphorylation of dark-adapted rhodopsin. A consequence of the latter behaviour of the activated kinase is that at low levels of bleach a large number of phosphoryl groups are incorporated per mol of Rho*. Recoverin- and Ca2+-dependent inhibition of rhodopsin kinase was found to be inversely related to the extent of bleaching; the lower the fraction of rhodopsin bleached, the greater the inhibition. The IC50 of recoverin is approx. 1 ƁM at a 0.2% level of bleach and about 5 ƁM in a fully bleached sample. The inhibitory effect of recoverin was studied separately on the phosphorylation of rhodopsin and Rho*. The formation of phosphorylated rhodopsin was inhibited 4.5-fold more strongly than that of phosphorylated Rho*. These results are interpreted to suggest that one of the roles of the recoverin-dependent regulation of the activity of rhodopsin kinase is to prevent the enzyme from participating in the unwanted phosphorylation of dark-adapted rhodopsin, directing it to fulfil its ‘correct’ function of quenching the transduction activity of Rho*.

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DEAN, Kevin R., und Muhammad AKHTAR. „Phosphorylatio of solubilised dark-adapted rhodopsin. Insights into the activation of rhodopsin kinase“. European Journal of Biochemistry 213, Nr. 2 (April 1993): 881–90. http://dx.doi.org/10.1111/j.1432-1033.1993.tb17832.x.

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Liu, Chang, Yichi Zhang, Yuqing Zhang, Zonghan Liu, Feifei Mao und Zongtao Chai. „Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A“. Molecules 27, Nr. 14 (21.07.2022): 4655. http://dx.doi.org/10.3390/molecules27144655.

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As a member of the death-associated protein kinase (DAPK) family, STK17B plays an important role in the regulation of cellular apoptosis and has been considered as a promising drug target for hepatocellular carcinoma. However, the highly conserved ATP-binding site of protein kinases represents a challenge to design selective inhibitors for a specific DAPK isoform. In this study, molecular docking, multiple large-scale molecular dynamics (MD) simulations, and binding free energy calculations were performed to decipher the molecular mechanism of the binding selectivity of PKIS43 toward STK17B against its high homology STK17A. MD simulations revealed that STK17A underwent a significant conformational arrangement of the activation loop compared to STK17B. The binding free energy predictions suggested that the driving force to control the binding selectivity of PKIS43 was derived from the difference in the protein–ligand electrostatic interactions. Furthermore, the per-residue free energy decomposition unveiled that the energy contribution from Arg41 at the phosphate-binding loop of STK17B was the determinant factor responsible for the binding specificity of PKIS43. This study may provide useful information for the rational design of novel and potent selective inhibitors toward STK17B.

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Tatar, Andra-Sorina, Timea Nagy-Simon, Adrian Bogdan Tigu, Ciprian Tomuleasa und Sanda Boca. „Optimization of Tyrosine Kinase Inhibitor-Loaded Gold Nanoparticles for Stimuli-Triggered Antileukemic Drug Release“. Journal of Functional Biomaterials 14, Nr. 8 (27.07.2023): 399. http://dx.doi.org/10.3390/jfb14080399.

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Tyrosine kinase inhibitor (TKI) therapy is gaining attraction in advanced cancer therapeutics due to the ubiquity of kinases in cell survival and differentiation. Great progress was made in the past years in identifying tyrosine kinases that can function as valuable molecular targets and for the entrapment of their corresponding inhibitors in delivery compounds for triggered release. Herein we present a class of drug-delivery nanocompounds based on TKI Midostaurin-loaded gold nanoparticles that have the potential to be used as theranostic agents for the targeting of the FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia. We optimized the nanocompounds’ formulation with loading efficiency in the 84–94% range and studied the drug release behavior in the presence of stimuli-responsive polymers. The therapeutic activity of MDS-loaded particles, superior to that of the free drug, was confirmed with toxicities depending on specific dosage ranges. No effect was observed on FLT3-negative cells or for the unloaded particles. Beyond druggability, we can track this type of nanocarrier inside biological structures as demonstrated via dark field microscopy. These properties might contribute to the facilitation of personalized drug dosage administration, critical for attaining a maximal therapeutic effect.

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Bronstein, Jeff, Claude G. Wasterlain, Robert Lasher und Debora B. Farber. „Dark-induced changes in activity and compartmentalization of retinal calmodulin kinase in the rat“. Brain Research 495, Nr. 1 (August 1989): 83–88. http://dx.doi.org/10.1016/0006-8993(89)91220-1.

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Min, Jeong Uk, Duck Young Heo und Sang Ho Kim. „The effect of the Intake Quantity of Dark Chocolate on the Aerobic Exercise Capacity, the Creatine Kinase Activity and Antioxidant Capacity“. Journal of Sport and Leisure Studies 51 (28.02.2013): 713–23. http://dx.doi.org/10.51979/kssls.2013.02.51.713.

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Žúbor, Vladimír, Albert Breier, Marta Horváthová, Dagmar Hagarová, Peter Gemeiner und Danica Mislovičová. „Purification of Glycerol Kinase by "Dye-Ligand" Chromatography and Hydrophobic Interaction Chromatography on Bead-Cellulose Derivatives“. Collection of Czechoslovak Chemical Communications 58, Nr. 2 (1993): 445–51. http://dx.doi.org/10.1135/cccc19930445.

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The crude extract of cytosole enzymes was obtained from homogenized cells of Saccharomyces cerevisiae by partition. The enzyme was then isolated from the lower aqueous phase displaying higher glycerol kinase activity by dye-ligand chromatography on Cibacron Blue (CB) or Remazol Brilliant Blue R (RB)-derivatized bead-cellulose, ATP being the eluent. The specific activity of glycerol kinase rised more than 10 and 7-times after affinity dye-ligand chromatography and hydrophobic interaction chromatography, respectively. Glycerol kinase obtained by the latter method was purified by CB-bead cellulose. The final preparation maintained its enzymic activity without noticeable losses during a long-term storage at 4 °C in dark.

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Frederiksen, Rikard, Soile Nymark, Alexander V. Kolesnikov, Justin D. Berry, Leopold Adler, Yiannis Koutalos, Vladimir J. Kefalov und M. Carter Cornwall. „Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods“. Journal of General Physiology 148, Nr. 1 (27.06.2016): 1–11. http://dx.doi.org/10.1085/jgp.201511538.

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Photoactivation of vertebrate rhodopsin converts it to the physiologically active Meta II (R*) state, which triggers the rod light response. Meta II is rapidly inactivated by the phosphorylation of C-terminal serine and threonine residues by G-protein receptor kinase (Grk1) and subsequent binding of arrestin 1 (Arr1). Meta II exists in equilibrium with the more stable inactive form of rhodopsin, Meta III. Dark adaptation of rods requires the complete thermal decay of Meta II/Meta III into opsin and all-trans retinal and the subsequent regeneration of rhodopsin with 11-cis retinal chromophore. In this study, we examine the regulation of Meta III decay by Grk1 and Arr1 in intact mouse rods and their effect on rod dark adaptation. We measure the rates of Meta III decay in isolated retinas of wild-type (WT), Grk1-deficient (Grk1−/−), Arr1-deficient (Arr1−/−), and Arr1-overexpressing (Arr1ox) mice. We find that in WT mouse rods, Meta III peaks ∼6 min after rhodopsin activation and decays with a time constant (τ) of 17 min. Meta III decay slows in Arr1−/− rods (τ of ∼27 min), whereas it accelerates in Arr1ox rods (τ of ∼8 min) and Grk1−/− rods (τ of ∼13 min). In all cases, regeneration of rhodopsin with exogenous 11-cis retinal is rate limited by the decay of Meta III. Notably, the kinetics of rod dark adaptation in vivo is also modulated by the levels of Arr1 and Grk1. We conclude that, in addition to their well-established roles in Meta II inactivation, Grk1 and Arr1 can modulate the kinetics of Meta III decay and rod dark adaptation in vivo.

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KOBAYASHI, Rumi, Yoshiharu SHIMOMURA, Taro MURAKAMI, Naoya NAKAI, Noriaki FUJITSUKA, Megumi OTSUKA, Nobuhiko ARAKAWA, M. Kirill POPOV und A. Robert HARRIS. „Gender difference in regulation of branched-chain amino acid catabolism“. Biochemical Journal 327, Nr. 2 (15.10.1997): 449–53. http://dx.doi.org/10.1042/bj3270449.

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Regulation of the activity state of the hepatic branched-chain 2-oxo acid dehydrogenase (BCODH) complex during the light-dark cycle differs markedly in male and female rats. Female rats exhibit a profound diurnal rhythm in the activity state of the complex that is not observed in male rats. Regardless of gender, most of the complex was dephosphorylated and active in the middle of the dark period and early in the light period, and this form of the complex predominated in male rats at the end of the light period. In contrast, most of the complex in female rats became phosphorylated and inactive by the end of the light period. Gonadectomy prevented the diurnal rhythm in females but was without effect in males, indicating that female sex hormones are required for this gender difference in regulation of the BCODH complex. Changes in levels of branched-chain 2-oxo acids, known regulators of BCODH kinase, do not seem to be involved; rather, an increase in BCODH kinase activity occurring between morning and evening is responsible for inactivation of the BCODH complex in female rats. The increase in kinase activity is due to an increase in the amount of kinase protein associated with the BCODH complex. Thus a marked diurnal variation in the amount of BCODH kinase and therefore its activity results in large swings in the activity state of the liver BCODH complex in female rats. This study provides the first evidence for a gender-specific difference in the regulation of branched-chain amino acid catabolism.

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Liepe, B. A., und B. Burnside. „Cyclic nucleotide regulation of teleost rod photoreceptor inner segment length.“ Journal of General Physiology 102, Nr. 1 (01.07.1993): 75–98. http://dx.doi.org/10.1085/jgp.102.1.75.

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Retinal rod photoreceptors of teleost fish elongate in the light and shorten in the dark. Rod cell elongation and shortening are both mediated by actin-dependent mechanisms that occur in the inner segment myoid and ellipsoid. The intracellular signaling pathways by which light and dark regulate the actin cytoskeleton in the inner segment are unknown. To investigate the intracellular signals that regulate teleost rod motility, we have been using mechanically isolated rod inner/outer segments (RIS-ROS) obtained from the retinas of green sunfish, Lepomis cyanellus. In culture, RIS-ROS retain the ability to elongate in response to light; myoids elongate 15-20 microns in length during 45 min of light culture. A pharmacological approach was taken to investigate the role of cyclic nucleotides, cyclic nucleotide-dependent kinases, and protein phosphatases in the regulation of RIS-ROS motility. Millimolar concentrations of cAMP and cGMP analogues were both found to inhibit light-induced myoid elongation and two cyclic nucleotide analogues, SpCAMPS and 8BrcGMP, promoted myoid shortening after RIS-ROS had elongated in response to light. The cyclic nucleotide-dependent kinase inhibitor, H8, mimicked light by promoting myoid elongation in the dark. The effects of H8 were dose dependent, with maximal elongation occurring at concentrations of approximately 100 microM. Similar to the effects of cyclic nucleotide analogues, the phosphatase inhibitor, okadaic acid (0.1-10 microM), inhibited light-induced elongation and promoted shortening. The results presented here suggest that RIS-ROS motility is regulated by protein phosphorylation: phosphorylation in the dark by cyclic nucleotide-dependent protein kinases promotes rod shortening, while dephosphorylation in the light promotes rod elongation.

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Priegnitz, Bert-Ewald, Ulrike Brandt, Khomaizon A. K. Pahirulzaman, Jeroen S. Dickschat und André Fleißner. „The AngFus3 Mitogen-Activated Protein Kinase Controls Hyphal Differentiation and Secondary Metabolism in Aspergillus niger“. Eukaryotic Cell 14, Nr. 6 (17.04.2015): 602–15. http://dx.doi.org/10.1128/ec.00018-15.

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ABSTRACTAdaptation to a changing environment is essential for the survival and propagation of sessile organisms, such as plants or fungi. Filamentous fungi commonly respond to a worsening of their growth conditions by differentiation of asexually or sexually produced spores. The formation of these specialized cell types is, however, also triggered as part of the general life cycle by hyphal age or density. Spores typically serve for dispersal and, therefore, translocation but can also act as resting states to endure times of scarcity. Eukaryotic differentiation in response to environmental and self-derived signals is commonly mediated by three-tiered mitogen-activated protein (MAP) kinase signaling cascades. Here, we report that the MAP kinase Fus3 of the black moldAspergillus niger(AngFus3) and its upstream kinase AngSte7 control vegetative spore formation and secondary metabolism. Mutants lacking these kinases are defective in conidium induction in response to hyphal density but are fully competent in starvation-induced sporulation, indicating that conidiation inA. nigeris triggered by various independent signals. In addition, the mutants exhibit an altered profile of volatile metabolites and secrete dark pigments into the growth medium, suggesting a dysregulation of the secondary metabolism. By assigning the AngFus3 MAP kinase pathway to the transduction of a potentially self-derived trigger, this work contributes to the unraveling of the intricate signaling networks controlling fungal differentiation. Moreover, our data further support earlier observations that differentiation and secondary metabolism are tightly linked in filamentous fungi.

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Sadiq, Nooruddin Bin, Hyukjoon Kwon, Nam Il Park, Muhammad Hamayun, Je-Hyeong Jung, Seung-Hoon Yang, Soo-Won Jang, Seda Nur Kabadayı, Ho-Youn Kim und Young-Joo Kim. „The Impact of Light Wavelength and Darkness on Metabolite Profiling of Korean Ginseng: Evaluating Its Anti-Cancer Potential against MCF-7 and BV-2 Cell Lines“. International Journal of Molecular Sciences 24, Nr. 9 (24.04.2023): 7768. http://dx.doi.org/10.3390/ijms24097768.

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Korean ginseng is a source of functional foods and medicines; however, its productivity is hindered by abiotic stress factors, such as light. This study investigated the impacts of darkness and different light wavelengths on the metabolomics and anti-cancer activity of ginseng extracts. Hydroponically-grown Korean ginseng was shifted to a light-emitting diodes (LEDs) chamber for blue-LED and darkness treatments, while white fluorescent (FL) light treatment was the control. MCF-7 breast cancer and lipopolysaccharide (LPS)-induced BV-2 microglial cells were used to determine chemo-preventive and neuroprotective potential. Overall, 53 significant primary metabolites were detected in the treated samples. The levels of ginsenosides Rb1, Rb2, Rc, Rd, and Re, as well as organic and amino acids, were significantly higher in the dark treatment, followed by blue-LED treatment and the FL control. The dark-treated ginseng extract significantly induced apoptotic signaling in MCF-7 cells and dose-dependently inhibited the NF-κB and MAP kinase pathways in LPS-induced BV-2 cells. Short-term dark treatment increased the content of Rd, Rc, Rb1, Rb2, and Re ginsenosides in ginseng extracts, which promoted apoptosis of MCF-7 cells and inhibition of the MAP kinase pathway in BV-2 microglial cells. These results indicate that the dark treatment might be effective in improving the pharmacological potential of ginseng.

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Donnelly, R. „Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research“. British Journal of Ophthalmology 88, Nr. 1 (01.01.2004): 145–51. http://dx.doi.org/10.1136/bjo.88.1.145.

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Zuniga, Freddi Isaac, Gina H. Ochoa, Shannon D. Kelly und Laura J. Robles. „S-crystallin and arginine kinase bind F-actin in light- and dark-adapted octopus retinas“. Current Eye Research 28, Nr. 5 (Januar 2004): 343–50. http://dx.doi.org/10.1076/ceyr.28.5.343.28683.

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Amrhein, Jennifer Alisa, Lena Marie Berger, Amelie Tjaden, Andreas Krämer, Lewis Elson, Tuomas Tolvanen, Daniel Martinez-Molina et al. „Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family“. International Journal of Molecular Sciences 23, Nr. 23 (27.11.2022): 14834. http://dx.doi.org/10.3390/ijms232314834.

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The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N-myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d, which exhibited high cellular potency for CDK16 (EC50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20–120 nM and 50–180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2/M phase cell cycle arrest at all tested concentrations for 43d, caused by inhibition of CDK16.

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Nakasako, Masayoshi, Mao Oide, Yuki Takayama, Tomotaka Oroguchi und Koji Okajima. „Domain Organization in Plant Blue-Light Receptor Phototropin2 of Arabidopsis thaliana Studied by Small-Angle X-ray Scattering“. International Journal of Molecular Sciences 21, Nr. 18 (10.09.2020): 6638. http://dx.doi.org/10.3390/ijms21186638.

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Phototropin2 (phot2) is a blue-light (BL) receptor protein that regulates the BL-dependent activities of plants for efficient photosynthesis. Phot2 is composed of two light-oxygen-voltage sensing domains (LOV1 and LOV2) to absorb BL, and a kinase domain. Photo-activated LOV domains, especially LOV2, play a major role in photo-dependent increase in the phosphorylation activity of the kinase domain. The atomic details of the overall structure of phot2 and the intramolecular mechanism to convert BL energy to a phosphorylation signal remain unknown. We performed structural studies on the LOV fragments LOV1, LOV2, LOV2-linker, and LOV2-kinase, and full-length phot2, using small-angle X-ray scattering (SAXS). The aim of the study was to understand structural changes under BL irradiation and discuss the molecular mechanism that enhance the phosphorylation activity under BL. SAXS is a suitable technique for visualizing molecular structures of proteins in solution at low resolution and is advantageous for monitoring their structural changes in the presence of external physical and/or chemical stimuli. Structural parameters and molecular models of the recombinant specimens were obtained from SAXS profiles in the dark, under BL irradiation, and after dark reversion. LOV1, LOV2, and LOV2-linker fragments displayed minimal structural changes. However, BL-induced rearrangements of functional domains were noted for LOV2-kinase and full-length phot2. Based on the molecular model together with the absorption measurements and biochemical assays, we discuss the intramolecular interactions and domain motions necessary for BL-enhanced phosphorylation activity of phot2.

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ADAMS, Ryan A., Xinran LIU, David S. WILLIAMS und Alexandra C. NEWTON. „Differential spatial and temporal phosphorylation of the visual receptor, rhodopsin, at two primary phosphorylation sites in mice exposed to light“. Biochemical Journal 374, Nr. 2 (01.09.2003): 537–43. http://dx.doi.org/10.1042/bj20030408.

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Phosphorylation of rhodopsin critically controls the visual transduction cascade by uncoupling it from the G-protein transducin. The kinase primarily responsible for this phosphorylation is rhodopsin kinase, a substrate-regulated kinase that phosphorylates light-activated rhodopsin. Protein kinase C has been implicated in controlling the phosphorylation of both light-activated and dark-adapted rhodopsin. Two of the major rhodopsin phosphorylation sites in vivo, Ser334 and Ser338, are effective protein kinase C phosphorylation sites in vitro, while the latter is preferentially phosphorylated by rhodopsin kinase in vitro. Using phosphospecific antibodies against each of these two sites, we show that both sites are under differential spatial and temporal regulation. Exposure of mice to light results in rapid phosphorylation of Ser338 that is evenly distributed along the rod outer segment. Phosphorylation of Ser334 is considerably slower, begins at the base of the rod outer segment, and spreads to the top of the photoreceptor over time. In addition, we show that phosphorylation of both sites is abolished in rhodopsin kinase−/− mice, revealing an absolute requirement for rhodopsin kinase to phosphorylate rhodopsin. This requirement may reflect the need for priming phosphorylations at rhodopsin kinase sites allowing for subsequent phosphorylation by protein kinase C at Ser334. In this regard, treatment of mouse retinas with phorbol esters results in a 4-fold increase in phosphorylation on Ser334, with no significant effect on the phosphorylation of Ser338. Our results are consistent with light triggering rapid priming phosphorylations of rhodopsin by rhodopsin kinase, followed by a slower phosphorylation on Ser334, which is regulated by protein kinase C.

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Tanaka, Susumu, Yoshiko Honda, Misa Sawachika, Kensuke Futani, Namika Yoshida und Tohru Kodama. „Degradation of STK16 via KCTD17 with Ubiquitin–Proteasome System in Relation to Sleep–Wake Cycle“. Kinases and Phosphatases 1, Nr. 1 (22.12.2022): 14–22. http://dx.doi.org/10.3390/kinasesphosphatases1010003.

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Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.

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Stitt, Mark, Gottfried Mieskes, Hans-Dieter Söling, Heike Große und Hans W. Heidt. „Diurnal Changes of Fructose-6-phosphate,2-kinase and Fructose-2,6-bis-phosphatase Activities in Spinach Leaves“. Zeitschrift für Naturforschung C 41, Nr. 3 (01.03.1986): 291–96. http://dx.doi.org/10.1515/znc-1986-0308.

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Extracts have been rapidly prepared from spinach leaves, and the activity of fructose-6-phosphate, 2-kinase (Fru6P,2kinase) and fructose-2,6-bisphosphatase (Fru2.6P2ase) measured. The enzyme activities do not change during light-dark transitions, but there is an increase of Fru6P,2- kinase and decrease of Fru2,6P2ase activity over several hours in the light. This increase of the Fru6P,2kinase: Fru2,6P2:ase ratio shows that a previously unrecognized mechanism, which may include protein modification, controls Fru2,6P2 levels in leaves. It operates as sucrose accumulates in the leaf, and will be involved in regulating the partitioning of photosynthate.

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Drewry, David H., Carrow I. Wells, William J. Zuercher und Timothy M. Willson. „A Perspective on Extreme Open Science: Companies Sharing Compounds without Restriction“. SLAS DISCOVERY: Advancing the Science of Drug Discovery 24, Nr. 5 (29.04.2019): 505–14. http://dx.doi.org/10.1177/2472555219838210.

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Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. This perspective describes how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. The integration of open science and kinase chemogenomics has supported the study of many new potential drug targets by the scientific community.

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Marcus, Daniel C., Hiroshi Sunose, Jianzhong Liu, Zhijun Shen und Margaret A. Scofield. „P2U purinergic receptor inhibits apical IsK/KvLQT1 channel via protein kinase C in vestibular dark cells“. American Journal of Physiology-Cell Physiology 273, Nr. 6 (01.12.1997): C2022—C2029. http://dx.doi.org/10.1152/ajpcell.1997.273.6.c2022.

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Vestibular dark cells (VDC) are known to electrogenically secrete K+ via slowly activating K+(IsK) channels, consisting of IsK regulatory and KvLQT1 channel subunits, and the associated short-circuit current ( I sc) is inhibited by agonists of the apical P2U(P2Y2) receptor (J. Liu, K. Kozakura, and D. C. Marcus. Audit. Neurosci. 2: 331–340, 1995). Measurements of relative K+ flux ( J K) with a self-referencing K+-selective probe demonstrated a decrease in J K after apical perfusion of 100 μM ATP. On-cell macropatch recordings from gerbil VDC showed a decrease of the IsKchannel current ( I IsK) by 83 ± 7% during pipette perfusion of 10 μM ATP. The magnitude of the decrease of I scby ATP was diminished in the presence of inhibitors of phospholipase C (PLC) and protein kinase C (PKC), U-73122 and GF109203X. Activation of PKC by phorbol 12-myristate 13-acetate (PMA, 20 nM) decreased I IsK by 79 ± 3% in perforated-patch whole cell recordings, whereas the inactive analog, 4α-PMA, had no effect. In contrast, elevation of cytosolic Ca2+ concentration by A-23187 increased the whole cell I IsK . The expression of the isk gene transcript was confirmed, and the serine responsible for the species-specific response to PKC was found to be present in the gerbil IsKsequence. These data provide evidence consistent with a direct effect of the PKC branch of the PLC pathway on the IsK channel of VDC in response to activation of the apical P2Ureceptor and predict that the secretion of endolymph in the human vestibular system may be controlled by PKC in the same way as in our animal model.

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Ling, Jun-Jie, Jian Li, Danmeng Zhu und Xing Wang Deng. „Noncanonical role of Arabidopsis COP1/SPA complex in repressing BIN2-mediated PIF3 phosphorylation and degradation in darkness“. Proceedings of the National Academy of Sciences 114, Nr. 13 (14.03.2017): 3539–44. http://dx.doi.org/10.1073/pnas.1700850114.

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The E3 ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) has been known to mediate key signaling factors for degradation via the ubiquitin/26S proteasome pathway in both plants and animals. Here, we report a noncanonical function of Arabidopsis COP1, the central repressor of photomorphogenesis, in the form of a COP1/ SUPPRESSOR of phyA-105 (SPA) complex. We show that the COP1/SPA complex associates with and stabilizes PHYTOCHROME INTERACTING FACTOR 3 (PIF3) to repress photomorphogenesis in the dark. We identify the GSK3-like kinase BRASSINOSTEROID-INSENSITIVE 2 (BIN2) as a kinase of PIF3, which induces PIF3 degradation via 26S proteasome during skotomorphogenesis. Mutations on two typical BIN2 phosphorylation motifs of PIF3 lead to a strong stabilization of the protein in the dark. We further show that the COP1/SPA complex promotes PIF3 stability by repressing BIN2 activity. Intriguingly, without affecting BIN2 expression, the COP1/SPA complex modulates BIN2 activity through interfering with BIN2–PIF3 interaction, thereby inhibiting BIN2-mediated PIF3 phosphorylation and degradation. Taken together, our results suggest another paradigm for COP1/SPA complex action in the precise control of skotomorphogenesis.

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Amiteye, Samuel, Kazuo Kobayashi, Daisuke Imamura, Shigeo Hosoya, Naotake Ogasawara und Tsutomu Sato. „Bacillus subtilis Diacylglycerol Kinase (DgkA) Enhances Efficient Sporulation“. Journal of Bacteriology 185, Nr. 17 (01.09.2003): 5306–9. http://dx.doi.org/10.1128/jb.185.17.5306-5309.2003.

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ABSTRACT The sn-1,2-diacylglycerol kinase homologue gene, dgkA, is a sporulation gene indispensable for the maintenance of spore stability and viability in Bacillus subtilis. After 6 h of growth in resuspension medium, the endospore morphology of the dgkA mutant by standard phase-contrast microscopy was normal; however, after 9 h, the endospores appeared mostly dark by phase-contrast microscopy, suggesting a defect in the spores. Moreover, electron microscopic studies revealed an abnormal cortex structure in mutant endospores 6 h after the onset of sporulation, an indication of cortex degeneration. In addition, a significant decrease in the dipicolinic acid content of mutant spores was observed. We also found that dgkA is expressed mainly during the vegetative phase. It seems likely that either the DgkA produced during growth prepares the cell for an essential step in sporulation or the enzyme persists into sporulation and performs an essential function.

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Dikiy, Igor, Uthama R. Edupuganti, Rinat R. Abzalimov, Peter P. Borbat, Madhur Srivastava, Jack H. Freed und Kevin H. Gardner. „Insights into histidine kinase activation mechanisms from the monomeric blue light sensor EL346“. Proceedings of the National Academy of Sciences 116, Nr. 11 (26.02.2019): 4963–72. http://dx.doi.org/10.1073/pnas.1813586116.

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Translation of environmental cues into cellular behavior is a necessary process in all forms of life. In bacteria, this process frequently involves two-component systems in which a sensor histidine kinase (HK) autophosphorylates in response to a stimulus before subsequently transferring the phosphoryl group to a response regulator that controls downstream effectors. Many details of the molecular mechanisms of HK activation are still unclear due to complications associated with the multiple signaling states of these large, multidomain proteins. To address these challenges, we combined complementary solution biophysical approaches to examine the conformational changes upon activation of a minimal, blue-light–sensing histidine kinase from Erythrobacter litoralis HTCC2594, EL346. Our data show that multiple conformations coexist in the dark state of EL346 in solution, which may explain the enzyme’s residual dark-state activity. We also observe that activation involves destabilization of the helices in the dimerization and histidine phosphotransfer-like domain, where the phosphoacceptor histidine resides, and their interactions with the catalytic domain. Similar light-induced changes occur to some extent even in constitutively active or inactive mutants, showing that light sensing can be decoupled from activation of kinase activity. These structural changes mirror those inferred by comparing X-ray crystal structures of inactive and active HK fragments, suggesting that they are at the core of conformational changes leading to HK activation. More broadly, our findings uncover surprising complexity in this simple system and allow us to outline a mechanism of the multiple steps of HK activation.

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ROY, DEBORAH R. SAMANTA, und COLIN J. BARNSTABLE. „Developmental expression of intracellular targets of cGMP in rat visual cortex and alteration with dark rearing“. Visual Neuroscience 18, Nr. 1 (Januar 2001): 109–18. http://dx.doi.org/10.1017/s0952523801181101.

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We describe the temporal pattern of mRNA expression of some of the molecular components of the NO/cGMP second messenger system in the developing rat visual cortex and the effect of dark rearing on their expression levels using semiquantitative RT-PCR. mRNA expression for these molecules was altered by dark rearing in one of three ways: (1) no change—rod, olfactory, and cone/testis CNG channels, nonselective cation channels gated by cyclic nucleotides and highly permeable to Ca2+; (2) decrease—cyclic nucleotide phosphodiesterases which regulate cyclic nucleotide levels, and soluble guanylyl cyclase, the key synthetic enzyme producing cGMP and potently activated by nitric oxide; and (3) increase—cGMP kinase I, a key enzyme activated by cGMP to phosphorylate a variety of intracellular proteins including cytoskeletal elements. These data suggest important and distinct roles for the cGMP system in both early and late developmental events in the rat visual cortex.

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Spicer, S. S., und B. A. Schulte. „Creatine kinase in epithelium of the inner ear.“ Journal of Histochemistry & Cytochemistry 40, Nr. 2 (Februar 1992): 185–92. http://dx.doi.org/10.1177/40.2.1313059.

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Epithelium of the inner ear in the gerbil and mouse was examined immunocytochemically for presence of creatine kinase (CK). Marginal cells of the cochlear stria vascularis and dark cells and transitional cells of the vestibular system were found to contain an abundance of the MM isozyme (MM-CK). CK in these cells concurs with that which is coupled to Na,K-ATPase in other cells and is considered to supply ATP for the Na,K-ATPase that mediates the high KCl of endolymph. Inner hair cells revealed content of the BB isozyme and in this respect resembled the energy-transducing photoreceptor cells in retina. In addition, outer phalangeal (Deiters') cells stained for both MM- and BB-CK whereas inner phalangeal cells evidenced content of only the BB isozyme. Immunolocalization of CK appeared similar in mouse and gerbil inner ear. Specificity of the staining was affirmed by observations in agreement with those reported for CK in various cell types and by staining with antisera from more than one source.

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Catelli, Arianna, Cristina Nanni, Rita Mulè, Pier Luigi Zinzani, Elena Sabattini, Marcello Lanari und Francesca Conti. „The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: A Story Rewritten through FDG-PET“. Journal of Clinical Medicine 13, Nr. 8 (11.04.2024): 2203. http://dx.doi.org/10.3390/jcm13082203.

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Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin’s lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation.

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Kowallik, Wolfgang, Meinolf Thiemann, Yi Huang, Gerard Mutumba, Lisa Beermann, Dagmar Broer und Norbert Grotjohann. „Complete Sequence of Glycolytic Enzymes in the Mycorrhizal Basidiomycete, Suillus bovinus“. Zeitschrift für Naturforschung C 53, Nr. 9-10 (01.10.1998): 818–27. http://dx.doi.org/10.1515/znc-1998-9-1007.

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Axenic cultures of Suillus bovinus were cultivated in inorganic liquid medium with glucose as a carbon source at 25 °C and continuous supply of oxygen by aeration with compressed air in the dark. Exogenous fructose as sole carbon source yielded about 50% less increase in dry weight than glucose. This resulted from different uptake velocities. Sucrose as sole exogenous carbon source yielded no measurable increase in dry weight. In glucose cultures, activities of all glycolytic enzymes were found. Maximum specific activities varied largely (from about 60 [fructose 6-phosphate kinase] to about 20 000 [triosephosphate isomerase] nmoles · mg protein-1 · min-1). Apparent Km-values also varied over more than two orders of magnitude (0.035 mᴍ [pyruvate kinase] to 6.16 mᴍ [triosephosphate isomerase]). Fructose 6-phosphate kinase proved to be the fructose 2,6-bisphosphate-regulated type, aldolase the divalent cation-dependent (class II) type and glyceratephosphate mutase the glycerate 2,3-phosphate-independent type of the respective enzymes. Eight of the 10 enzymes exhibited pʜ-optima′ between 7.5-8.0. Triosephosphate isomerase and pyruvate kinase showed highest activities at pʜ 6.5. Regulatory sites within the glycolytic pathway of Suillus bovinus are discussed; fructose 6-phosphate kinase appears to be its main bottle neck.

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Shin, Na-Hyun, Do Thi Trang, Woo-Jong Hong, Kiyoon Kang, Jadamba Chuluuntsetseg, Joon-Kwan Moon, Yo-Han Yoo, Ki-Hong Jung und Soo-Cheul Yoo. „Rice Senescence-Induced Receptor-Like Kinase (OsSRLK) Is Involved in Phytohormone-Mediated Chlorophyll Degradation“. International Journal of Molecular Sciences 21, Nr. 1 (30.12.2019): 260. http://dx.doi.org/10.3390/ijms21010260.

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Chlorophyll breakdown is a vital catabolic process of leaf senescence as it allows the recycling of nitrogen and other nutrients. In the present study, we isolated rice senescence-induced receptor-like kinase (OsSRLK), whose transcription was upregulated in senescing rice leaves. The detached leaves of ossrlk mutant (ossrlk) contained more green pigment than those of the wild type (WT) during dark-induced senescence (DIS). HPLC and immunoblot assay revealed that degradation of chlorophyll and photosystem II proteins was repressed in ossrlk during DIS. Furthermore, ultrastructural analysis revealed that ossrlk leaves maintained the chloroplast structure with intact grana stacks during dark incubation; however, the retained green color and preserved chloroplast structures of ossrlk did not enhance the photosynthetic competence during age-dependent senescence in autumn. In ossrlk, the panicles per plant was increased and the spikelets per panicle were reduced, resulting in similar grain productivity between WT and ossrlk. By transcriptome analysis using RNA sequencing, genes related to phytohormone, senescence, and chlorophyll biogenesis were significantly altered in ossrlk compared to those in WT during DIS. Collectively, our findings indicate that OsSRLK may degrade chlorophyll by participating in a phytohormone-mediated pathway.

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Kolesnikov, Alexander V., Tivadar Orban, Hui Jin, Celine Brooks, Lukas Hofmann, Zhiqian Dong, Maxim Sokolov, Krzysztof Palczewski und Vladimir J. Kefalov. „Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors“. Proceedings of the National Academy of Sciences 114, Nr. 45 (23.10.2017): E9675—E9684. http://dx.doi.org/10.1073/pnas.1712405114.

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Resetting of G-protein–coupled receptors (GPCRs) from their active state back to their biologically inert ground state is an integral part of GPCR signaling. This “on–off” GPCR cycle is regulated by reversible phosphorylation. Retinal rod and cone photoreceptors arguably represent the best-understood example of such GPCR signaling. Their visual pigments (opsins) are activated by light, transduce the signal, and are then inactivated by a GPCR kinase and arrestin. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain unknown. Here, we show that protein phosphatase 2A (PP2A) acts as opsin phosphatase in both rods and cones. Elimination of PP2A substantially slows pigment dephosphorylation, visual chromophore recycling, and ultimately photoreceptor dark adaptation. These findings demonstrate that visual pigment dephosphorylation regulates the dark adaptation of photoreceptors and provide insights into the role of this reaction in GPCR signaling.

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Long, Brit, Elisha Targonsky und Alex Koyfman. „Just the Facts: Diagnosis and management of rhabdomyolysis“. CJEM 22, Nr. 6 (11.05.2020): 745–48. http://dx.doi.org/10.1017/cem.2020.37.

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A 32-year-old male presents with diffuse myalgias, weakness, and dark urine for 1 day. The patient states he recently started a new exercise program. He is hemodynamically stable, and his physical examination reveals diffuse muscle tenderness. His creatine kinase (CK) returns at 8,000 international units per liter (IU/L), and his urinalysis reveals blood but only three red blood cells (RBCs) on microscopy.

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García-Domínguez, M., M. I. Muro-Pastor, J. C. Reyes und F. J. Florencio. „Light-Dependent Regulation of Cyanobacterial Phytochrome Expression“. Journal of Bacteriology 182, Nr. 1 (01.01.2000): 38–44. http://dx.doi.org/10.1128/jb.182.1.38-44.2000.

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ABSTRACT A histidine kinase protein (Cph1) with sequence homology and spectral characteristics very similar to those of the plant phytochrome has been recently identified in the cyanobacteriumSynechocystis sp. strain PCC 6803. Cph1 together with Rcp1 (a protein homologue to the response regulator CheY) forms a light-regulated two-component system whose function is presently unknown. Levels of cph1 rcp1 mRNA increase in the dark and decrease upon reillumination. A dark-mediated increase in cph1 rcp1 mRNA levels was inhibited by the presence of glucose, but not by inhibition of the photosynthetic electron flow. The half-life ofcph1 rcp1 transcript in the light was about fourfold shorter than in the dark, indicating that control of cph1 rcp1 transcript stability is one of the mechanisms by which light regulates expression of the cyanobacterial phytochrome. After 15 min of darkness, 3-min pulses of red, blue, green, and far-red light were equally efficient in decreasing the cph1 rcp1 mRNA levels. Red light downregulation was not reversed by far-red light, suggesting that cph1 rcp1 mRNA levels are not controlled by a phytochrome-like photoreceptor. Furthermore, aSynechocystis strain containing an H538R Cph1 point mutation, unable to phosphorylate Rcp1, shows normal light-dark regulation of the cph1 rcp1 transcript levels. Our data suggest a role of cyanobacterial phytochrome in the control of processes required for adaptation in light-dark and dark-light transitions.

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Slater, T. F., K. H. Cheeseman, C. Benedetto, M. Collins, S. Emery, S. P. Maddix, J. T. Nodes, K. Proudfoot, G. W. Burton und K. U. Ingold. „Studies on the hyperplasia (‘regeneration’) of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects“. Biochemical Journal 265, Nr. 1 (01.01.1990): 51–59. http://dx.doi.org/10.1042/bj2650051.

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Using the experimental model of partial hepatectomy in the rat, we have examined the relationship between cell division and lipid peroxidation activity. In rats entrained to a regime of 12 h light/12 h dark and with a fixed 8 h feeding period in the dark phase, partial hepatectomy is followed by a rapid regeneration of liver mass with cycles of synchronized cell division at 24 h intervals. The latter phenomenon is indicated in this study by pulses of thymidine kinase activity having maxima at 24 h, 48 h and 72 h after partial hepatectomy. Microsomes prepared from regenerating livers show changes in lipid peroxidation activity (induced by NADPH/ADP/iron or by ascorbate/iron), which is significantly decreased relative to that in microsomes from sham-operated controls, again at 24 h, 48 h and 72 h after the operation. This phenomenon has been investigated with regard to possible underlying changes in the content of microsomal fatty acids, the microsomal enzymes NADPH:cytochrome c reductase and cytochrome P-450, and the physiological microsomal antioxidant alpha-tocopherol. The cycles of decreased lipid peroxidation activity are apparently due, at least in part, to changes in microsomal alpha-tocopherol content that are closely associated in time with thymidine kinase activity.

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