Academic literature on the topic 'Glycolysis. Protein kinases Phosphorylation Metabolism'
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Journal articles on the topic "Glycolysis. Protein kinases Phosphorylation Metabolism"
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Horlock, Anthony D., Thomas J. R. Ormsby, Martin J. D. Clift, José E. P. Santos, John J. Bromfield, and I. Martin Sheldon. "Manipulating bovine granulosa cell energy metabolism limits inflammation." Reproduction 161, no. 5 (May 2021): 499–512. http://dx.doi.org/10.1530/rep-20-0554.
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Bovine granulosa cells are often exposed to energy stress, due to the energy demands of lactation, and exposed to lipopolysaccharide from postpartum bacterial infections. Granulosa cells mount innate immune responses to lipopolysaccharide, including the phosphorylation of mitogen-activated protein kinases and production of pro-inflammatory interleukins. Cellular energy depends on glycolysis, and energy stress activates intracellular AMPK (AMP-activated protein kinase), which in turn inhibits mTOR (mechanistic target of rapamycin). Here, we tested the hypothesis that manipulating glycolysis, AMPK or mTOR to mimic energy stress in bovine granulosa cells limits the inflammatory responses to lipopolysaccharide. We inhibited glycolysis, activated AMPK or inhibited mTOR in granulosa cells isolated from 4–8mm and from > 8.5 mm diameter ovarian follicles, and then challenged the cells with lipopolysaccharide and measured the production of interleukins IL-1α, IL-1β, and IL-8. We found that inhibiting glycolysis with 2-deoxy-d-glucose reduced lipopolysaccharide-stimulated IL-1α > 80%, IL-1β > 90%, and IL-8 > 65% in granulosa cells from 4–8 mm and from > 8.5 mm diameter ovarian follicles. Activating AMPK with AICAR also reduced lipopolysaccharide-stimulated IL-1α > 60%, IL-1β > 75%, and IL-8 > 20%, and shortened the duration of lipopolysaccharide-stimulated phosphorylation of the mitogen-activated protein kinase ERK1/2 and JNK. However, only the mTOR inhibitor Torin 1, and not rapamycin, reduced lipopolysaccharide-stimulated IL-1α and IL-1β. In conclusion, manipulating granulosa cell energy metabolism with a glycolysis inhibitor, an AMPK activator, or an mTOR inhibitor, limited inflammatory responses to lipopolysaccharide. Our findings imply that energy stress compromises ovarian follicle immune defences.
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Chou, Po-Chien, Swati Rajput, Xiaoyun Zhao, Chadni Patel, Danielle Albaciete, Won Jun Oh, Heineken Queen Daguplo, et al. "mTORC2 Is Involved in the Induction of RSK Phosphorylation by Serum or Nutrient Starvation." Cells 9, no. 7 (June 27, 2020): 1567. http://dx.doi.org/10.3390/cells9071567.
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Cells adjust to nutrient fluctuations to restore metabolic homeostasis. The mechanistic target of rapamycin (mTOR) complex 2 responds to nutrient levels and growth signals to phosphorylate protein kinases belonging to the AGC (Protein Kinases A,G,C) family such as Akt and PKC. Phosphorylation of these AGC kinases at their conserved hydrophobic motif (HM) site by mTORC2 enhances their activation and mediates the functions of mTORC2 in cell growth and metabolism. Another AGC kinase family member that is known to undergo increased phosphorylation at the homologous HM site (Ser380) is the p90 ribosomal S6 kinase (RSK). Phosphorylation at Ser380 is facilitated by the activation of the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) in response to growth factor stimulation. Here, we demonstrate that optimal phosphorylation of RSK at this site requires an intact mTORC2. We also found that RSK is robustly phosphorylated at Ser380 upon nutrient withdrawal or inhibition of glycolysis, conditions that increase mTORC2 activation. However, pharmacological inhibition of mTOR did not abolish RSK phosphorylation at Ser380, indicating that mTOR catalytic activity is not required for this phosphorylation. Since RSK and SIN1β colocalize at the membrane during serum restimulation and acute glutamine withdrawal, mTORC2 could act as a scaffold to enhance RSK HM site phosphorylation. Among the known RSK substrates, the CCTβ subunit of the chaperonin containing TCP-1 (CCT) complex had defective phosphorylation in the absence of mTORC2. Our findings indicate that the mTORC2-mediated phosphorylation of the RSK HM site could confer RSK substrate specificity and reveal that RSK responds to nutrient fluctuations.
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Jaswal, Jagdip S., Manoj Gandhi, Barry A. Finegan, Jason R. B. Dyck, and Alexander S. Clanachan. "Effects of adenosine on myocardial glucose and palmitate metabolism after transient ischemia: role of 5′-AMP-activated protein kinase." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 4 (October 2006): H1883—H1892. http://dx.doi.org/10.1152/ajpheart.01147.2005.
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Loss of cardioprotection by adenosine in hearts stressed by transient ischemia may be due to its effects on glucose metabolism. In the absence of transient ischemia, adenosine inhibits glycolysis, whereas it accelerates glycolysis after transient ischemia. Inasmuch as 5′-AMP-activated protein kinase (AMPK) is implicated as a regulator of glucose and fatty acid utilization, this study determined whether a differential alteration of AMPK activity contributes to acceleration of glycolysis by adenosine in hearts stressed by transient ischemia. Studies were performed in working rat hearts perfused aerobically under normal conditions or after transient ischemia (two 10-min periods of ischemia followed by 5 min of reperfusion). LV work was not affected by adenosine. AMPK phosphorylation was not affected by transient ischemia; however, phosphorylation and activity were increased nine- and threefold, respectively, by adenosine in stressed hearts. Phosphorylation of acetyl-CoA carboxylase and rates of palmitate oxidation were unaltered. Glycolysis and calculated proton production were increased 1.8- and 1.7-fold, respectively, in hearts with elevated AMPK activity. Elevated AMPK activity was associated with inhibition of glycogen synthesis and unchanged rates of glucose uptake and glycogenolysis. Phentolamine, an α-adrenoceptor antagonist, which prevents adenosine-induced activation of glycolysis in stressed hearts, prevented AMPK phosphorylation. These data demonstrate that adenosine-induced activation of AMPK after transient ischemia is not sufficient to alter palmitate oxidation or glucose uptake. Rather, activation of AMPK alters partitioning of glucose away from glycogen synthesis; the increase in glycolysis may in part contribute to loss of adenosine-induced cardioprotection in hearts subjected to transient ischemia.
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Che, Pulin, Lei Yu, Gregory K. Friedman, Meimei Wang, Xiaoxue Ke, Huafeng Wang, Wenbin Zhang, Burt Nabors, Qiang Ding, and Xiaosi Han. "Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells." Cancers 13, no. 5 (March 5, 2021): 1111. http://dx.doi.org/10.3390/cancers13051111.
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Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.
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Miwa, Hiroshi, Kazuto Suganuma, Masato Shikami, Norikazu Imai, Mayuko Sakai, Akihito Hiramatsu, Hidesuke Yamamoto, et al. "Energy Metabolism of Leukemia Cells: Glycolysis Vs Oxidative Phosphorylation." Blood 112, no. 11 (November 16, 2008): 2935. http://dx.doi.org/10.1182/blood.v112.11.2935.2935.
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Abstract Cancer cells are more dependent on glycolysis than oxidative phosphorylation in the mitochondria for generation of ATP as energy source. By using 2-deoxy-D-glucose (2-DG: glycolysis inhibitor) and oligomycin (inhibitor of oxidative phosphorylation), we examined the energy metabolism of various leukemia cell lines. The growth of the cell lines was measured by MTS assay, which detects viable cells in proliferation. 2-DG suppressed the growth of all leukemia cell lines examined in dose-dependent manners. The IC50 of each cell line was as follows: Kasumi-1 0.5±0.1mM, KG-1a 1.8±0.6mM, HL-60 3.3±0.1mM, NB4 3.8±0.4mM, and THP-1 23.1±3.8mM. The concentration of lactic acid (the final product of glycolytic pathway) in the culture supernatant was greatly reduced by the treatment with 0.2mM 2-DG for 24 hours in Kasumi-1 (54.5% of the control), compared with THP-1 (92.2%). It is suggested that the growth of Kasumi-1 was strongly suppressed by 2-DG through inhibition of glycolysis, which is supposed to be a main metabolic pathway in this cell line. On the other hand, treatment with oligomycin (1μg/ml) for 48 hours potently suppressed the growth of THP-1 (44.7%), then Kasumi-1 (72.1%). The growth of NB4, KG-1a and HL-60 was minimally suppressed (more than 90%) by oligomycin. Cell cycle was analyzed after 24 hours treatment with 2-DG or oligomycin. Sub-G1 fraction (apoptosis) was greatly increased by 2-DG (5mM) in Kasumi-1 (56.5%) and NB4 (30.6%), compared with THP-1 (7.6%). The apoptosis inducing effect was confirmed by annexinV staining. Oligomycin treatment (1μg/ml) increased apoptosis (subG1) in THP-1 (35.8%), then Kasumi-1 (16.6%) and NB4 (12.2%). Oligomycin treatment also increased G1 population (G1 arrest) in THP-1 (35.9% to 69.4%). AMP-activated protein kinase (AMPK) is activated by an elevated AMP/ATP ratio, which means the energy-deprived status of the cell. Western blot analysis using phospho-AMPK α (Thr172) antibody revealed that treatment with 2-DG or oligomycin induced prompt (30 min) phosphorylation of AMPK in leukemia cell lines. The extent of AMPK phosphorylation was almost proportional to the suppression of the growth. Collectively, it is suggested that leukemia cells are dependent almost exclusively on either glycolysis or oxidative phosphorylation in the mitochondria for energy production. Then, inhibition of glycolysis by 2-DG or oxidative phosphorylation by oligomycin results in growth suppression by inducing apoptosis and/or cell cycle arrest through activation of AMPK. Our data clarified the characteristics of the energy metabolism of each leukemia cell, and showed the key to produce novel therapeutic approach targeting metabolic pathway.
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He, Nanhai, Weiwei Fan, Brian Henriquez, Ruth T. Yu, Annette R. Atkins, Christopher Liddle, Ye Zheng, Michael Downes, and Ronald M. Evans. "Metabolic control of regulatory T cell (Treg) survival and function by Lkb1." Proceedings of the National Academy of Sciences 114, no. 47 (November 6, 2017): 12542–47. http://dx.doi.org/10.1073/pnas.1715363114.
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The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance.
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Rodríguez-Enríquez, Sara, Álvaro Marín-Hernández, Juan Carlos Gallardo-Pérez, Silvia Cecilia Pacheco-Velázquez, Javier Alejandro Belmont-Díaz, Diana Xochiquetzal Robledo-Cadena, Jorge Luis Vargas-Navarro, Norma Angélica Corona de la Peña, Emma Saavedra, and Rafael Moreno-Sánchez. "Transcriptional Regulation of Energy Metabolism in Cancer Cells." Cells 8, no. 10 (October 9, 2019): 1225. http://dx.doi.org/10.3390/cells8101225.
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Cancer development, growth, and metastasis are highly regulated by several transcription regulators (TRs), namely transcription factors, oncogenes, tumor-suppressor genes, and protein kinases. Although TR roles in these events have been well characterized, their functions in regulating other important cancer cell processes, such as metabolism, have not been systematically examined. In this review, we describe, analyze, and strive to reconstruct the regulatory networks of several TRs acting in the energy metabolism pathways, glycolysis (and its main branching reactions), and oxidative phosphorylation of nonmetastatic and metastatic cancer cells. Moreover, we propose which possible gene targets might allow these TRs to facilitate the modulation of each energy metabolism pathway, depending on the tumor microenvironment.
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Ding, Hao, Lei Jiang, Jing Xu, Feng Bai, Yang Zhou, Qi Yuan, Jing Luo, Ke Zen, and Junwei Yang. "Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis." American Journal of Physiology-Renal Physiology 313, no. 3 (September 1, 2017): F561—F575. http://dx.doi.org/10.1152/ajprenal.00036.2017.
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Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy.
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Kuranaga, Yuki, Nobuhiko Sugito, Haruka Shinohara, Takuya Tsujino, Kohei Taniguchi, Kazumasa Komura, Yuko Ito, Tomoyoshi Soga, and Yukihiro Akao. "SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells." International Journal of Molecular Sciences 19, no. 10 (October 2, 2018): 3012. http://dx.doi.org/10.3390/ijms19103012.
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Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.
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Murugina, Nina E., Anna S. Budikhina, Yulia A. Dagil, Polina V. Maximchik, Lyudmila S. Balyasova, Vladimir V. Murugin, Mikhail V. Melnikov, et al. "Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: No association with proinflammatory cytokine production in normoxia." Journal of Biological Chemistry 295, no. 10 (January 31, 2020): 3099–114. http://dx.doi.org/10.1074/jbc.ra119.010589.
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Upon activation with pathogen-associated molecular patterns, metabolism of macrophages and dendritic cells is shifted from oxidative phosphorylation to aerobic glycolysis, which is considered important for proinflammatory cytokine production. Fragments of bacterial peptidoglycan (muramyl peptides) activate innate immune cells through nucleotide-binding oligomerization domain (NOD) 1 and/or NOD2 receptors. Here, we show that NOD1 and NOD2 agonists induce early glycolytic reprogramming of human monocyte-derived macrophages (MDM), which is similar to that induced by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide. This glycolytic reprogramming depends on Akt kinases, independent of mTOR complex 1 and is efficiently inhibited by 2-deoxy-d-glucose (2-DG) or by glucose starvation. 2-DG inhibits proinflammatory cytokine production by MDM and monocyte-derived dendritic cells activated by NOD1 or TLR4 agonists, except for tumor necrosis factor production by MDM, which is inhibited initially, but augmented 4 h after addition of agonists and later. However, 2-DG exerts these effects by inducing unfolded protein response rather than by inhibiting glycolysis. By contrast, glucose starvation does not cause unfolded protein response and, in normoxic conditions, only marginally affects proinflammatory cytokine production triggered through NOD1 or TLR4. In hypoxia mimicked by treating MDM with oligomycin (a mitochondrial ATP synthase inhibitor), both 2-DG and glucose starvation strongly suppress tumor necrosis factor and interleukin-6 production and compromise cell viability. In summary, the requirement of glycolytic reprogramming for proinflammatory cytokine production in normoxia is not obvious, and effects of 2-DG on cytokine responses should be interpreted cautiously. In hypoxia, however, glycolysis becomes critical for cytokine production and cell survival.
Dissertations / Theses on the topic "Glycolysis. Protein kinases Phosphorylation Metabolism"
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Ellingson, William J. "The effects of 3-phosphoglycerate and other metabolites on the activation of AMP-activated protein kinase by LKB1/STRAD/MO25 /." Diss., CLICK HERE for online access, 2006. http://contentdm.lib.byu.edu/ETD/image/etd1406.pdf.
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Prinos, Panagiotis. "Purification and characterization of a mammalian DNA kinase." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55524.
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Using a novel purification scheme and a new assay for detection of DNA kinase activity, a Polymin P-precipitable DNA kinase has been identified and characterized from calf thymus extracts. The DNA kinase activity was able to phosphorylate RNA as well as single-stranded and double-stranded DNA, therefore it has been termed Polymin P-precipitable polynucleotide kinase (PP-PNK). The enzyme had a neutral to alkaline, broad pH optimum that distinguished it from the previously described mammalian DNA kinases that have an acidic pH optimum. The sedimentation coefficient of the enzyme was 3.4-3.8 S, indicating a molecular weight of about 50 kDa. Estimates for the K$ sb{ rm M}$ for ATP were 52 $ mu$M and for the oligonucleotide substrate 8 $ mu$M. The activity was inhibited by pyrophosphate anions and to a lesser extent by sulfate anions. These results differentiate PP-PNK from other mammalian polynucleotide kinases.
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Slack, Carolyn. "Molecular studies of a mammalian DNA kinase." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23938.
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Whole cell extracts from fresh calf thymus glands were subjected to Polymin P fractionation and Q Sepharose chromatography. Three peaks of DNA kinase activity, designated SNQI, SNQII and SNQIII, were found in the supernatant fraction. Studies of SNQI have revealed an estimated molecular mass of 50-90 kDa by Superose 12 chromatography, and activity gel analysis following SDS-PAGE identified an active polypeptide of approximately 55 kDa. This enzyme preparation, purified 10,000-fold, phosphorylated 5$ sp prime$-OH-terminated oligodeoxyribonucleotides and double stranded DNA, yet was inactive on an oligoriboadenosine ladder. SNQI functions optimally at an acidic pH in 10 mM MgCl$ sb2$, but is inhibited by both sulfate and pyrophosphate anions. The estimated K$ sb{ rm M}$ values were 2.3 $ mu$M for the oligonucleotide substrate and 11.8 $ mu$M for ATP. Similar to an enzymatic activity previously isolated from rat liver, SNQI is the first bovine preparation to display both 5$ sp prime$ kinase and 3$ sp prime$ phosphatase activities.Partial purification and characterization of SNQII revealed similarities to SNQI, such as an acidic pH optimum and the presence of 3$ sp prime$ phosphatase activity. DNA kinase activity was also demonstrated in two mammalian cell lines.
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Cheng, Sam Xian Jun. "Functional significance of phosphorylation of rat renal Na+,K+-ATPase by PKA and PKC /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2971-8.
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Cardin, Eric. "Function of Nck-1 adaptor protein as modulator of elF2alpha phosphorylation by specific elF2alpha kinases and PKR activity." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111905.
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Phosphorylation of the alpha-subunit of the eukaryotic initiation factor 2 (eIF2alpha) on Serine 51 (Ser51) is an early event associated with downregulation of protein synthesis at the level of translation and constitutes a potent mechanism to overcome various stress conditions. In mammals, four eIF2alpha-kinases PERK, PKR, HRI and GCN2, activated following specific stresses, have been involved in this process. Our laboratory has previously demonstrated that the adaptor protein Nck, composed only of Src homology domains and classically implicated in cell signaling by activated plasma membrane receptor tyrosine kinases, modulates translation through its interaction with the beta-subunit of the eukaryotic initiation factor 2 (eIF2beta). Moreover, we reported that Nck-1 overexpression antagonizes the inhibition of translation in endoplasmic reticulum stress condition and prevents the PERK-mediated phosphorylation of the alpha-subunit of eIF2 on Ser51. In this thesis, I demonstrate that the adaptor protein Nck-1 modulates eIF2alpha-kinase-mediated eIF2alphaSer51 phosphorylation in a specific manner. More particularly, I show that Nck-1 overexpression reduces eIF2alpha phosphorylation in conditions activating PKR or HRI as described previously for PERK. In contrast, I observe that overexpression of Nck-1 in mammalian cells fails to attenuate eIF2alphaSer51 phosphorylation in response to amino acid starvation, a stress condition activating GCN2. I further confirm this observation by showing that Nck-1 fails to alter eIF2alphaSer51 phosphorylation in Saccharomyces cerevisiae, for which the sole eIF2alpha-kinase is GCN2. In addition, I report that Nck-1 reduces PKR activation in response to dsRNA. I also find that Nck-1 reduces dsRNA-induced activation of p38 MAPK, a PKR-downstream substrate, and cell death. Finally, I show that Nck-1 interacts exclusively with the inactivated form of PKR in a Src homology domain independent manner. All together these data uncover the existence of a novel mechanism regulating phosphorylation of eIF2alphaSer51 under various stress conditions and identifies Nck-1 as a modulator of the tumor suppressor and antiviral protein kinase PKR.
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Domise, Manon. "Rôle de la dérégulation neuronale de la protéine kinase activée par l’AMP (AMPK) dans la pathologie tau, l’intégrité des synapses et le métabolisme énergétique : relevance pour la maladie d’Alzheimer." Thesis, Lille 2, 2018. http://www.theses.fr/2018LIL2S034/document.
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La maladie d'Alzheimer (MA) est une pathologie neurodégénérative principalement caractérisée par la présence de dépôts amyloïdes et d'enchevêtrements neurofibrillaires composés de protéines tau hyperphosphorylées. Tau est une protéine associée aux microtubules qui possède de nombreux sites de phosphorylation pouvant être phosphorylés par différentes kinases. En plus de la pathologie tau, on observe également dans le cerveau des patients atteints de la MA, une apparition précoce d’altérations métaboliques ainsi qu’une perte synaptique qui est à l’origine du développement des troubles cognitifs. En effet, les synapses sont des connexions neuronales essentielles pour la formation de la mémoire qui nécessitent une importante quantité d’énergie pour maintenir leurs fonctions. Depuis plusieurs années, des études suggèrent que l’AMPK – senseur métabolique essentiel des cellules – pourrait être impliquée dans le développement de la MA. En effet, des travaux réalisés in vitro ont permis de montrer que l’AMPK est une kinase de tau. Par ailleurs, il a été mis en évidence que chez les patients atteints de la MA, l’AMPK est dérégulée dans les neurones en dégénérescence où elle co-localise avec les protéines tau hyperphosphorylées. Enfin, des études menées dans notre équipe ont également permis de mettre en évidence que suite à une activation synaptique, l'AMPK restaure les niveaux d'énergie des neurones laissant ainsi supposer qu'une dérégulation de son activité pourrait avoir un impact néfaste sur le métabolisme neuronal. Au vu de ces données, les objectifs de mon projet de thèse ont donc été de déterminer l'impact d'une dérégulation de l’AMPK neuronale sur la pathologie tau, la perte synaptique et le métabolisme énergétique neuronal dans un modèle de culture primaire de neurones et in vivo chez la souris. La réalisation de ces objectifs nous a permis de démontrer (1) que l'AMPK régule la phosphorylation et la pathologie tau, (2) que la dérégulation de l’AMPK induit une diminution du nombre des synapses ainsi qu'une perte de la fonctionnalité du réseau neuronal, via une voie de signalisation impliquant l’autophagie et (3) que la dérégulation de l’AMPK entraine des perturbations du métabolisme énergétique neuronal. En conclusion, ce travail de thèse a permis d’apporter une meilleure compréhension sur le rôle de la dérégulation de l’AMPK dans le développement des différentes caractéristiques de la MA. Dans l’ensemble, ces données laissent fortement suggérer que l’AMPK pourrait faire le lien entre les dysfonctionnements métaboliques et l’ensemble des altérations qui se mettent en place au cours de la MAAlzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by the presence of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Tau is a microtubule-associated protein that bears many phosphorylation sites which can be phosphorylated by different kinases. Beside tau pathology, AD is also characterized by cerebral metabolic alterations and synaptic loss, the latter being responsible for the development of cognitive disorders. Indeed, synapses are essential for memory formation and require a large amount of energy to maintain their functions. Interestingly, studies have suggested that AMP-activated protein kinase (AMPK) – a crucial intracellular metabolic sensor – could be involved in the development of AD. Indeed, in vitro studies have shown that AMPK is a tau kinase. In addition, AMPK is deregulated in degenerating neurons of AD patients brain where it co-localizes with hyperphosphorylated tau proteins. Additionally, studies carried out in our team showed that upon synaptic activation, AMPK activity is essential to maintain neuronal energy levels thus suggesting that a deregulation of its activity could have harmful impact on neuronal metabolism. On the basis of these data, the objectives of this thesis were to determine the impact of neuronal AMPK deregulation on tau pathology, synaptic loss and neuronal energy metabolism in primary neurons and in vivo in mice. The achievement of these objectives allowed us to demonstrate (1) that AMPK regulated tau phosphorylation and pathology (2) that AMPK deregulation caused a decrease of synapses number as well as a loss of neuronal networks functionality, through a signaling pathway involving autophagy and (3) that AMPK deregulation impacted on neuronal energy metabolism. In conclusion, this thesis has provided a better understanding of the role of AMPK deregulation in the development of different hallmarks of AD. Altogether, these data strongly suggest that AMPK could be the link between neuronal metabolism dysfunctions and the development of the alteration that occur during AD
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"Biochemical and genetic analysis of Tau protein kinases in drosophila." 2005. http://library.cuhk.edu.hk/record=b5892391.
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Chau Wing-Kam.Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 92-101).
Abstracts in English and Chinese.
Abstract --- p.I
Abstract (Chinese version) --- p.III
Acknowledgement --- p.IV
List of Abbreviations --- p.VIII
List of Tables --- p.IX
List of Figures --- p.X
Chapter Chapter 1 --- Introduction
Chapter 1.1 --- Neurodegenerative diseases --- p.2
Chapter 1.2 --- Tauopathies --- p.5
Chapter 1.3 --- Function and structure of Tau --- p.9
Chapter 1.4 --- Post-translational modifications of Tau --- p.13
Chapter 1.5 --- Tau protein kinases --- p.17
Chapter 1.6 --- Tau protein kinase inhibitors --- p.19
Chapter 1.7 --- Drosophila model of Tauopathies --- p.20
Chapter 1.8 --- Aims of study --- p.24
Chapter Chapter 2 --- Materials and methods
Chapter 2.1 --- Drosophila manipulation
Chapter 2.1.1 --- Drosophila genetics --- p.26
Chapter 2.1.2 --- External fly eye and adult wing morphology examination --- p.27
Chapter 2.1.3 --- Study of fly wings deformation on Tau kinase overexpression --- p.27
Chapter 2.2 --- RNA extraction
Chapter 2.2.1 --- Method --- p.28
Chapter 2.2.2 --- Buffers and reagents --- p.29
Chapter 2.3 --- Reverse transcription-PCR
Chapter 2.3.1 --- Method --- p.30
Chapter 2.3.2 --- Buffers and reagents --- p.31
Chapter 2.4 --- SDS-Polyacrylamide gel electrophoresis
Chapter 2.4.1 --- Method --- p.31
Chapter 2.4.2 --- Buffers and reagents --- p.32
Chapter 2.5 --- Western blotting
Chapter 2.5.1 --- Method --- p.32
Chapter 2.5.2 --- Buffers and reagents --- p.33
Chapter 2.6 --- Phosphatase treatment of proteins
Chapter 2.6.1 --- Method --- p.34
Chapter 2.6.2 --- Buffers and reagents --- p.34
Chapter 2.7 --- Sequential extraction of proteins
Chapter 2.7.1 --- Methods --- p.35
Chapter 2.7.2 --- Buffers and reagents --- p.36
Chapter 2.8 --- Sarkosyl extraction of proteins
Chapter 2.8.1 --- Method --- p.37
Chapter 2.8.2 --- Buffers and reagents --- p.37
Chapter 2.9 --- Immunostaining
Chapter 2.9.1 --- Method --- p.38
Chapter 2.9.2 --- Buffers and reagents --- p.38
Chapter 2.10 --- Lithium treatment of flies
Chapter 2.10.1 --- Method --- p.39
Chapter 2.10.2 --- Buffers and reagents --- p.40
Chapter 2.11 --- Quantitation of Lithium ion by atomic absorption spectrometry
Chapter 2.11.1 --- Method --- p.40
Chapter 2.12 --- Statistical analysis --- p.41
Chapter Chapter 3 --- Results
Chapter 3.1 --- GAL4/UAS gene expression system in transgenic fly
Chapter 3.1.1 --- Introduction --- p.43
Chapter 3.1.2 --- Results --- p.47
Chapter 3.1.3 --- Discussion --- p.52
Chapter 3.2 --- Tau phosphorylation and Tau-induced toxicity in transgenic fly
Chapter 3.2.1 --- Introduction --- p.52
Chapter 3.2.2 --- Results
Chapter 3.2.2.1 --- Overexpressed Tau is phosphorylated and toxic in fly --- p.53
Chapter 3.2.2.2 --- Coexpression of GSK3β/Shaggy or Cdk5 enhance Tau phosphorylation and Tau-induced toxicity --- p.57
Chapter 3.2.2.3 --- Lithium suppresses Tau phosphorylation and Tau-induced toxicity --- p.64
Chapter 3.2.3 --- Discussion --- p.68
Chapter 3.3 --- Tau solubility properties in transgenic fly
Chapter 3.3.1 --- Introduction --- p.69
Chapter 3.3.2 --- Results
Chapter 3.3.2.1 --- Coexpression of GSKlβ/Shaggy does not alter the sarkosyl solubility of Tau --- p.70
Chapter 3.3.2.2 --- Coexpression of GSK3β/Shaggy causes a minor alteration of Tau solubility properties --- p.73
Chapter 3.3.3 --- Discussion --- p.78
Chapter 3.4 --- Tau aggregate formation in transgenic fly
Chapter 3.4.1 --- Introduction --- p.79
Chapter 3.4.2 --- Results
Chapter 3.4.2.1 --- Tau aggregates are detected in aged transgenic flies --- p.80
Chapter 3.4.3 --- Discussion --- p.82
Chapter 3.5 --- Effect of Lithium on GSK3p/Shaggy-induced wing deformation
Chapter 3.5.1 --- Introduction --- p.83
Chapter 3.5.2 --- Results
Chapter 3.5.2.1 --- Lithium rescues GSK3β/Shaggy-induced wing deformation --- p.84
Chapter 3.5.3 --- Discussion --- p.86
Chapter Chapter 4 --- General discussion --- p.87
References --- p.92
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Schmidl, Sebastian. "Pathogenicity of a minimal organism: Role of protein phosphorylation in Mycoplasma pneumoniae." Thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-ADDA-4.
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Kickstein, E., S. Krauss, P. Thornhill, D. Rutschow, R. Zeller, J. Sharkey, Ritchie Williamson, et al. "Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling." 2010. http://hdl.handle.net/10454/6051.
Full textAbstract:
Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-alpha4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.
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Fox, Melanie Joy. "The role of Rtr1 and Rrp6 in RNAPII in transcription termination." 2015. http://hdl.handle.net/1805/7372.
Full textAbstract:
Indiana University-Purdue University Indianapolis (IUPUI)RNA Polymerase II (RNAPII) is responsible for transcription of messenger RNA (mRNA) and many small non-coding RNAs. Progression through the RNAPII transcription cycle is orchestrated by combinatorial posttranslational modifications of the C-terminal domain (CTD) of the largest subunit of RNAPII, Rpb1, consisting of the repetitive sequence (Y1S2P3T4S5P6S7)n. Disruptions of proteins that control CTD phosphorylation, including the phosphatase Rtr1, cause defects in gene expression and transcription termination. There are two described RNAPII termination mechanisms. Most mRNAs are terminated by the polyadenylation-dependent cleavage and polyadenylation complex. Most short noncoding RNAs are terminated by the Nrd1 complex. Nrd1-dependent termination is coupled to RNA 3' end processing and/or degradation by Rrp6, a nuclear specific subunit of the exosome. The Rrp6-containing form a 3'-5' exonuclease complex that regulates diverse aspects of nuclear RNA biology including 3' end processing and degradation of a variety of noncoding RNAs (ncRNAs). It remains unclear whether Rrp6 is directly involved in termination. We discovered that deletion of RRP6 promotes extension of multiple Nrd1-dependent transcripts resulting from improperly processed 3' RNA ends and faulty transcript termination at specific target genes. Defects in RNAPII termination cause transcriptome-wide changes in mRNA expression through transcription interference and/or antisense repression, similar to previously reported effects of Nrd1 depletion from the nucleus. Our data indicate Rrp6 acts with Nrd1 globally to promote transcription termination in addition to RNA processing and/or degradation. Furthermore, we found that deletion of the CTD phosphatase Rtr1 shortens the distance of transcription before Nrd1-dependent termination of specific regulatory antisense transcripts (ASTs), increases Nrd1 occupancy at these sites, and increases the interaction between Nrd1 and RNAPII. The RTR1/RRP6 double deletion phenocopies an RRP6 deletion, indicating that the regulation of ASTs by Rtr1 requires Rrp6 activity and the Nrd1 termination pathway.
Books on the topic "Glycolysis. Protein kinases Phosphorylation Metabolism"
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G, Hardie D., ed. Protein phosphorylation: A practical approach. Oxford: Oxford University Press, 1993.
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J, Clemens Michael, ed. Protein phosphorylation in cell growth regulation. Australia: Harwood Academic Publishers, 1996.
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Hardie, D. Grahame. Protein Phosphorylation: A Practical Approach (Practical Approach Series). Oxford University Press, USA, 1993.
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Hardie, D. Grahame. Protein Phosphorylation: A Practical Approach (Practical Approach Series). Oxford University Press, USA, 1993.
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1943-, Kalinski Michael I., ed. Exercise and intracellular regulation of cardiac and skeletal muscle. Champaign, IL: Human Kinetics, 1995.
Find full textBook chapters on the topic "Glycolysis. Protein kinases Phosphorylation Metabolism"
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Zhan, Xianquan, and Na Li. "The Anti-Cancer Effects of Anti-Parasite Drug Ivermectin in Ovarian Cancer." In Ovarian Cancer - Updates in Tumour Biology and Therapeutics [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95556.
Full textAbstract:
Ivermectin is an old, common, and classic anti-parasite drug, which has been found to have a broad-spectrum anti-cancer effect on multiple human cancers. This chapter will focus on the anti-cancer effects of ivermectin on ovarian cancer. First, ivermectin was found to suppress cell proliferation and growth, block cell cycle progression, and promote cell apoptosis in ovarian cancer. Second, drug pathway network, qRT-PCR, and immunoaffinity blot analyses found that ivermectin acts through molecular networks to target the key molecules in energy metabolism pathways, including PFKP in glycolysis, IDH2 and IDH3B in Kreb’s cycle, ND2, ND5, CYTB, and UQCRH in oxidative phosphorylation, and MCT1 and MCT4 in lactate shuttle, to inhibit ovarian cancer growth. Third, the integrative analysis of TCGA transcriptomics and mitochondrial proteomics in ovarian cancer revealed that 16 survival-related lncRNAs were mediated by ivermectin, SILAC quantitative proteomics analysis revealed that ivermectin extensively inhibited the expressions of RNA-binding protein EIF4A3 and 116 EIF4A3-interacted genes including those key molecules in energy metabolism pathways, and also those lncRNAs regulated EIF4A3-mRNA axes. Thus, ivermectin mediated lncRNA-EIF4A3-mRNA axes in ovarian cancer to exert its anticancer capability. Further, lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565), which is significantly associated with overall survival and clinicopathologic characteristics in ovarian cancer patients. These ivermectin-related molecular pattern alterations benefit for prognostic assessment and personalized drug therapy toward 3P medicine practice in ovarian cancer.