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1
Hohmann, Stefan. "Osmotic Stress Signaling and Osmoadaptation in Yeasts." Microbiology and Molecular Biology Reviews 66, no. 2 (June 2002): 300–372. http://dx.doi.org/10.1128/mmbr.66.2.300-372.2002.
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SUMMARY The ability to adapt to altered availability of free water is a fundamental property of living cells. The principles underlying osmoadaptation are well conserved. The yeast Saccharomyces cerevisiae is an excellent model system with which to study the molecular biology and physiology of osmoadaptation. Upon a shift to high osmolarity, yeast cells rapidly stimulate a mitogen-activated protein (MAP) kinase cascade, the high-osmolarity glycerol (HOG) pathway, which orchestrates part of the transcriptional response. The dynamic operation of the HOG pathway has been well studied, and similar osmosensing pathways exist in other eukaryotes. Protein kinase A, which seems to mediate a response to diverse stress conditions, is also involved in the transcriptional response program. Expression changes after a shift to high osmolarity aim at adjusting metabolism and the production of cellular protectants. Accumulation of the osmolyte glycerol, which is also controlled by altering transmembrane glycerol transport, is of central importance. Upon a shift from high to low osmolarity, yeast cells stimulate a different MAP kinase cascade, the cell integrity pathway. The transcriptional program upon hypo-osmotic shock seems to aim at adjusting cell surface properties. Rapid export of glycerol is an important event in adaptation to low osmolarity. Osmoadaptation, adjustment of cell surface properties, and the control of cell morphogenesis, growth, and proliferation are highly coordinated processes. The Skn7p response regulator may be involved in coordinating these events. An integrated understanding of osmoadaptation requires not only knowledge of the function of many uncharacterized genes but also further insight into the time line of events, their interdependence, their dynamics, and their spatial organization as well as the importance of subtle effects.
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Ismail, Alaa, Ahmed Salah, Adel Guirgis, Shaden Muawia, and Hany Khalil. "Glycerol-mediated lysosomal associated proteins as a novel anticancer theory in colon cancer cell line." Journal of Internal Medicine: Science & Art 4 (May 25, 2023): 2–10. http://dx.doi.org/10.36013/jimsa.v4i.110.
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Background: Colon cancer begins in the large intestine (colon) and is aggressive due to late diagnosis, so there is a poor prognosis and higher mortality rates, as reported. Colon cancer has become a vital research area requiring more investigation of cellular signaling in its initiation and development. Aim: The study aimed to investigate the biological effects of Glycerol in cell proliferation and the possible regulation of cellular signaling by exogenous treatment of Glycerol in colon cancer cells compared with colon mucosal epithelial cells.
Materials and Methods: The influence of Glycerol on cell viability rate was monitored by inverted microscopy, and the number of living cells was assessed upon incubation with different concentrations of Glycerol. We further inspected the apoptotic rate of CaCo-2 cells by using Annexin-V staining by flow cytometry. Moreover, we achieved the expression profile of lysosomal-associated proteins, LAMP-1 and LAMP-2, in treated cells using qRT-PCR and flow cytometry. Finally, we monitored the released pro-inflammatory cytokines and anti-inflammatory in response to Glycerol treatment using ELISA assay.
Results: Our results showed that Glycerol treatment could prevent cancer cell proliferation without any detectable cytotoxic occurrence in the normal cells. Interestingly, we evidenced that Glycerol targets and breaks down the lysosomal activities by inhibiting the expression profile of both LAMP-1 and LAMP-2. Furthermore, Glycerol treatment successfully adjusted the production of IL-6 and IL-8 as pro-inflammatory cytokines while stimulating the production of anti-inflammatory cytokines, IL-4 and IL-10, in a time-dependent manner.
Conclusion: These data provide evidence for the anti-cancer properties of Glycerol in colon cancer cells via targeting lysosomal activities and disturbance of the degradation events in colon cancer cells.
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Allmann, Stefan, Marion Wargnies, Nicolas Plazolles, Edern Cahoreau, Marc Biran, Pauline Morand, Erika Pineda, et al. "Glycerol suppresses glucose consumption in trypanosomes through metabolic contest." PLOS Biology 19, no. 8 (August 13, 2021): e3001359. http://dx.doi.org/10.1371/journal.pbio.3001359.
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Microorganisms must make the right choice for nutrient consumption to adapt to their changing environment. As a consequence, bacteria and yeasts have developed regulatory mechanisms involving nutrient sensing and signaling, known as “catabolite repression,” allowing redirection of cell metabolism to maximize the consumption of an energy-efficient carbon source. Here, we report a new mechanism named “metabolic contest” for regulating the use of carbon sources without nutrient sensing and signaling. Trypanosoma brucei is a unicellular eukaryote transmitted by tsetse flies and causing human African trypanosomiasis, or sleeping sickness. We showed that, in contrast to most microorganisms, the insect stages of this parasite developed a preference for glycerol over glucose, with glucose consumption beginning after the depletion of glycerol present in the medium. This “metabolic contest” depends on the combination of 3 conditions: (i) the sequestration of both metabolic pathways in the same subcellular compartment, here in the peroxisomal-related organelles named glycosomes; (ii) the competition for the same substrate, here ATP, with the first enzymatic step of the glycerol and glucose metabolic pathways both being ATP-dependent (glycerol kinase and hexokinase, respectively); and (iii) an unbalanced activity between the competing enzymes, here the glycerol kinase activity being approximately 80-fold higher than the hexokinase activity. As predicted by our model, an approximately 50-fold down-regulation of the GK expression abolished the preference for glycerol over glucose, with glucose and glycerol being metabolized concomitantly. In theory, a metabolic contest could be found in any organism provided that the 3 conditions listed above are met.
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Krantz, Marcus, Bodil Nordlander, Hadi Valadi, Mikael Johansson, Lena Gustafsson, and Stefan Hohmann. "Anaerobicity Prepares Saccharomyces cerevisiae Cells for Faster Adaptation to Osmotic Shock." Eukaryotic Cell 3, no. 6 (December 2004): 1381–90. http://dx.doi.org/10.1128/ec.3.6.1381-1390.2004.
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ABSTRACT Yeast cells adapt to hyperosmotic shock by accumulating glycerol and altering expression of hundreds of genes. This transcriptional response of Saccharomyces cerevisiae to osmotic shock encompasses genes whose products are implicated in protection from oxidative damage. We addressed the question of whether osmotic shock caused oxidative stress. Osmotic shock did not result in the generation of detectable levels of reactive oxygen species (ROS). To preclude any generation of ROS, osmotic shock treatments were performed in anaerobic cultures. Global gene expression response profiles were compared by employing a novel two-dimensional cluster analysis. The transcriptional profiles following osmotic shock under anaerobic and aerobic conditions were qualitatively very similar. In particular, it appeared that expression of the oxidative stress genes was stimulated upon osmotic shock even if there was no apparent need for their function. Interestingly, cells adapted to osmotic shock much more rapidly under anaerobiosis, and the signaling as well as the transcriptional response was clearly attenuated under these conditions. This more rapid adaptation is due to an enhanced glycerol production capacity in anaerobic cells, which is caused by the need for glycerol production in redox balancing. Artificially enhanced glycerol production led to an attenuated response even under aerobic conditions. These observations demonstrate the crucial role of glycerol accumulation and turgor recovery in determining the period of osmotic shock-induced signaling and the profile of cellular adaptation to osmotic shock.
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Zhang, Zhao, Diana M. Iglesias, Rachel Corsini, LeeLee Chu, and Paul Goodyer. "WNT/β-Catenin Signaling Is Required for Integration of CD24+Renal Progenitor Cells into Glycerol-Damaged Adult Renal Tubules." Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/391043.
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During development, nephron progenitor cells (NPC) are induced to differentiate by WNT9b signals from the ureteric bud. Although nephrogenesis ends in the perinatal period, acute kidney injury (AKI) elicits repopulation of damaged nephrons. Interestingly, embryonic NPC infused into adult mice with AKI are incorporated into regenerating tubules. Since WNT/β-catenin signaling is crucial for primary nephrogenesis, we reasoned that it might also be needed for the endogenous repair mechanism and for integration of exogenous NPC. When we examined glycerol-induced AKI in adult mice bearing aβ-catenin/TCF reporter transgene, endogenous tubular cells reexpressed the NPC marker, CD24, and showed widespreadβ-catenin/TCF signaling. We isolated CD24+cells from E15 kidneys of mice with the canonical WNT signaling reporter. 40% of cells responded to WNT3ain vitroand when infused into glycerol-injured adult, the cells exhibitedβ-catenin/TCF reporter activity when integrated into damaged tubules. When embryonic CD24+cells were treated with aβ-catenin/TCF pathway inhibitor (IWR-1) prior to infusion into glycerol-injured mice, tubular integration of cells was sharply reduced. Thus, the endogenous canonicalβ-catenin/TCF pathway is reactivated during recovery from AKI and is required for integration of exogenous embryonic renal progenitor cells into damaged tubules. These events appear to recapitulate the WNT-dependent inductive process which drives primary nephrogenesis.
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Nath, Karl A., John D. Belcher, Meryl C. Nath, Joseph P. Grande, Anthony J. Croatt, Allan W. Ackerman, Zvonimir S. Katusic, and Gregory M. Vercellotti. "Role of TLR4 signaling in the nephrotoxicity of heme and heme proteins." American Journal of Physiology-Renal Physiology 314, no. 5 (May 1, 2018): F906—F914. http://dx.doi.org/10.1152/ajprenal.00432.2017.
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Destabilized heme proteins release heme, and free heme is toxic. Heme is now recognized as an agonist for the Toll-like receptor-4 (TLR4) receptor. This study examined whether the TLR4 receptor mediates the nephrotoxicity of heme, specifically, the effects of heme on renal blood flow and inflammatory responses. We blocked TLR4 signaling by the specific antagonist TAK-242. Intravenous administration of heme to mice promptly reduced renal blood flow, an effect attenuated by TAK-242. In vitro, TAK-242 reduced heme-elicited activation of NF-κB and its downstream gene monocyte chemoattractant protein-1(MCP-1); in contrast, TAK-242 failed to reduce heme-induced activation of the anti-inflammatory transcription factor Nrf2 and its downstream gene heme oxygenase-1 (HO-1). TAK-242 did not reduce heme-induced renal MCP-1 upregulation in vivo. TAK-242 did not reduce dysfunction and histological injury in the glycerol model of heme protein-induced acute kidney injury (AKI), findings corroborated by studies in TLR4+/+ and TLR4−/− mice. We conclude that 1) acute heme-mediated renal vasoconstriction occurs through TLR4 signaling; 2) proinflammatory effects of heme in renal epithelial cells involve TLR4 signaling, whereas the anti-inflammatory effects of heme do not; 3) TLR4 signaling does not mediate the proinflammatory effects of heme in the kidney; and 4) major mechanisms underlying glycerol-induced, heme protein-mediated AKI do not involve TLR4 signaling. These findings in the glycerol model are in stark contrast with findings in virtually all other AKI models studied to date and emphasize the importance of TLR4-independent pathways of heme protein-mediated injury in this model. Finally, these studies urge caution when using observations derived in vitro to predict what occurs in vivo.
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Mugabo, Yves, Shangang Zhao, Julien Lamontagne, Anfal Al-Mass, Marie-Line Peyot, Barbara E. Corkey, Erik Joly, S. R. Murthy Madiraju, and Marc Prentki. "Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells." Journal of Biological Chemistry 292, no. 18 (March 9, 2017): 7407–22. http://dx.doi.org/10.1074/jbc.m116.763060.
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Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to triglycerides and cholesterol esters.
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Zeng, Changjun, Keyi Tang, Lian He, Wenpei Peng, Li Ding, Donghui Fang, and Yan Zhang. "Effects of glycerol on apoptotic signaling pathways during boar spermatozoa cryopreservation." Cryobiology 68, no. 3 (June 2014): 395–404. http://dx.doi.org/10.1016/j.cryobiol.2014.03.008.
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Bełtowski, Jerzy, and Krzysztof Wiórkowski. "Role of Hydrogen Sulfide and Polysulfides in the Regulation of Lipolysis in the Adipose Tissue: Possible Implications for the Pathogenesis of Metabolic Syndrome." International Journal of Molecular Sciences 23, no. 3 (January 25, 2022): 1346. http://dx.doi.org/10.3390/ijms23031346.
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Hydrogen sulfide (H2S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in the adipose tissue. We examined the effect of H2S and polysulfides on adipose tissue lipolysis. H2S and polysulfide production by mesenteric adipose tissue explants in rats was measured. The effect of Na2S and Na2S4, the H2S and polysulfide donors, respectively, on lipolysis markers, plasma non-esterified fatty acids (NEFA) and glycerol, was examined. Na2S but not Na2S4 increased plasma NEFA and glycerol in a time- and dose-dependent manner. Na2S increased cyclic AMP but not cyclic GMP concentration in the adipose tissue. The effect of Na2S on NEFA and glycerol was abolished by the specific inhibitor of protein kinase A, KT5720. The effect of Na2S on lipolysis was not abolished by propranolol, suggesting no involvement of β-adrenergic receptors. In addition, Na2S had no effect on phosphodiesterase activity in the adipose tissue. Obesity induced by feeding rats a highly palatable diet for 1 month was associated with increased plasma NEFA and glycerol concentrations, as well as greater H2S production in the adipose tissue. In conclusion, H2S stimulates lipolysis and may contribute to the enhanced lipolysis associated with obesity.
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Krycer, James R., Lake-Ee Quek, Deanne Francis, Armella Zadoorian, Fiona C. Weiss, Kristen C. Cooke, Marin E. Nelson, et al. "Insulin signaling requires glucose to promote lipid anabolism in adipocytes." Journal of Biological Chemistry 295, no. 38 (July 28, 2020): 13250–66. http://dx.doi.org/10.1074/jbc.ra120.014907.
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Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.
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Zager, Richard A., and Ali C. M. Johnson. "Acute kidney injury induces dramatic p21 upregulation via a novel, glucocorticoid-activated, pathway." American Journal of Physiology-Renal Physiology 316, no. 4 (April 1, 2019): F674—F681. http://dx.doi.org/10.1152/ajprenal.00571.2018.
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The cyclin kinase inhibitor p21 is acutely upregulated during acute kidney injury (AKI) and exerts cytoprotective effects. A proposed mechanism is oxidant stress-induced activation of p53, the dominant p21 transcription factor. Glycerol-induced rhabdomyolysis induces profound renal oxidant stress. Hence, we studied this AKI model to determine whether p53 activation corresponds with p21 gene induction and/or whether alternative mechanism(s) might be involved. CD-1 mice were subjected to glycerol-induced AKI. After 4 or 18 h, plasma, urinary, and renal cortical p21 protein and mRNA levels were assessed. Renal p53 activation was gauged by measurement of both total and activated (Ser15-phosphorylated) p53 and p53 mRNA levels. Glycerol evoked acute, progressive increases in renal cortical p21 mRNA and protein levels. Corresponding plasma (~25-fold) and urinary (~75-fold) p21 elevations were also observed. Renal cortical ratio of total to phosphorylated (Ser15) p53 rose three- to fourfold. However, the p53 inhibitor pifithrin-α failed to block glycerol-induced p21 gene induction, suggesting that an alternative p21 activator might also be at play. To this end, it was established that glycerol-induced AKI 1) dramatically increased plasma (~5-fold) and urinary (~75-fold) cortisol levels, 2) the glucocorticoid receptor antagonist mifepristone blocked glycerol-induced p21 mRNA and protein accumulation, and 3) dexamethasone or cortisol injections markedly increased p21 protein and mRNA in both normal and glycerol-treated mice, although no discernible p53 protein or mRNA increases were observed. We conclude that AKI-induced “systemic stress” markedly increases plasma and urinary cortisol, which can then activate renal p21 gene expression, at least in part, via a glucocorticoid receptor-dependent signaling pathway. Discernible renal cortical p53 increases are not required for this dexamethasone-mediated p21 response.
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Mugabo, Yves, Shangang Zhao, Annegrit Seifried, Sari Gezzar, Anfal Al-Mass, Dongwei Zhang, Julien Lamontagne, et al. "Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic β-cells and hepatocytes." Proceedings of the National Academy of Sciences 113, no. 4 (January 11, 2016): E430—E439. http://dx.doi.org/10.1073/pnas.1514375113.
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Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet β-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3-phosphate (Gro3P) and fatty acyl-CoA. We describe here a mammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet β-cells and hepatocytes, and that glucose stimulated insulin secretion and the response to metabolic stress, e.g., glucolipotoxicity, in β-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders.
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Miermont, Agnès, Jannis Uhlendorf, Megan McClean, and Pascal Hersen. "The Dynamical Systems Properties of the HOG Signaling Cascade." Journal of Signal Transduction 2011 (February 7, 2011): 1–12. http://dx.doi.org/10.1155/2011/930940.
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The High Osmolarity Glycerol (HOG) MAP kinase pathway in the budding yeast Saccharomyces cerevisiae is one of the best characterized model signaling pathways. The pathway processes external signals of increased osmolarity into appropriate physiological responses within the yeast cell. Recent advances in microfluidic technology coupled with quantitative modeling, and techniques from reverse systems engineering have allowed yet further insight into this already well-understood pathway. These new techniques are essential for understanding the dynamical processes at play when cells process external stimuli into biological responses. They are widely applicable to other signaling pathways of interest. Here, we review the recent advances brought by these approaches in the context of understanding the dynamics of the HOG pathway signaling.
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Zhang, Michael S., Aline Sandouk, and Jon C. D. Houtman. "Glycerol Monolaurate (GML) inhibits human T cell signaling, metabolism, and function by disrupting lipid dynamics." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 57.4. http://dx.doi.org/10.4049/jimmunol.196.supp.57.4.
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Abstract Glycerol Monolaurate (GML) is a naturally occurring fatty acid widely utilized in food, cosmetics, and homeopathic supplements. GML is a potent antimicrobial agent that targets a range of bacteria, fungi, and enveloped viruses. Interestingly, GML suppresses mitogen induced lymphocyte proliferation and inositol triphosphate production, suggesting that GML has immunomodulatory functions. In this study, we have mechanistically examined if GML affects the signaling, metabolism, and functional output of human primary T cells. We found that GML potently altered lipid order and disorder dynamics in the plasma membrane that resulted in reduced membrane localized clustering of the proteins LAT, PLC-γ, and AKT, events integral for proper T cell receptor (TCR) signal propagation. Altered membrane signaling events induced selective inhibition of TCR-induced phosphorylation of SLP-76, regulatory P85 subunit of PI3K, and AKT as well as abrogated calcium influx. In addition to signaling defects, GML treated cells have profoundly altered metabolism profiles characterized by suppressed oxidative phosphorylation and increased glycolysis. Functionally, GML treatment potently reduced TCR-induced production of the cytokines IL-2, IFN-γ, TNF-α, and IL-10. Our data reveal that the widely used anti-microbial agent GML alters the lipid dynamics of human T cells, leading to their defective signaling, metabolism, and function.
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Santos, Ronaldo Silva, Gabriel Martins-Silva, Adrián Adolfo Álvarez Padilla, Mateus Possari, Sérgio Donnantuoni Degello, Otávio J. Bernardes Brustolini, Ana Tereza Ribeiro Vasconcelos, Marcelo Afonso Vallim, and Renata C. Pascon. "Transcriptional and Post-Translational Roles of Calcineurin in Cationic Stress and Glycerol Biosynthesis in Cryptococcus neoformans." Journal of Fungi 10, no. 8 (July 30, 2024): 531. http://dx.doi.org/10.3390/jof10080531.
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Stress management is an adaptive advantage for survival in adverse environments. Pathogens face this challenge during host colonization, requiring an appropriate stress response to establish infection. The fungal pathogen Cryptococcus neoformans undergoes thermal, oxidative, and osmotic stresses in the environment and animal host. Signaling systems controlled by Ras1, Hog1, and calcineurin respond to high temperatures and osmotic stress. Cationic stress caused by Na+, K+, and Li+ can be overcome with glycerol, the preferred osmolyte. Deleting the glycerol phosphate phosphatase gene (GPP2) prevents cells from accumulating glycerol due to a block in the last step of its biosynthetic pathway. Gpp2 accumulates in a phosphorylated form in a cna1Δ strain, and a physical interaction between Gpp2 and Cna1 was found; moreover, the gpp2Δ strain undergoes slow growth and has attenuated virulence in animal models of infection. We provide biochemical evidence that growth in 1 M NaCl increases glycerol content in the wild type, whereas gpp2Δ, cna1Δ, and cnb1Δ mutants fail to accumulate it. The deletion of cnb1Δ or cna1Δ renders yeast cells sensitive to cationic stress, and the Gfp-Gpp2 protein assumes an abnormal localization. We suggest a mechanism in which calcineurin controls Gpp2 at the post-translational level, affecting its localization and activity, leading to glycerol biosynthesis. Also, we showed the transcriptional profile of glycerol-deficient mutants and established the cationic stress response mediated by calcineurin; among the biological processes differentially expressed are carbon utilization, translation, transmembrane transport, glutathione metabolism, oxidative stress response, and transcription regulation. To our knowledge, this is the first time that this transcriptional profile has been described. These results have implications for pathogen stress adaptability.
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Song, Tengyao, Qiongyu Hao, Yun-Min Zheng, Qing-Hua Liu, and Yong-Xiao Wang. "Inositol 1,4,5-trisphosphate activates TRPC3 channels to cause extracellular Ca2+ influx in airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 12 (December 15, 2015): L1455—L1466. http://dx.doi.org/10.1152/ajplung.00148.2015.
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Transient receptor potential-3 (TRPC3) channels play a predominant role in forming nonselective cation channels (NSCCs) in airway smooth muscle cells (ASMCs) and are significantly increased in their activity and expression in asthmatic ASMCs. To extend these novel findings, we have explored the regulatory mechanisms that control the activity of TRPC3 channels. Our data for the first time reveal that inositol 1,4,5-trisphosphate (IP3), an important endogenous signaling molecule, can significantly enhance the activity of single NSCCs in ASMCs. The analog of diacylglycerol (DAG; another endogenous signaling molecule), 1-oleyl-2-acetyl- sn-glycerol (OAG), 1-stearoyl-2-arachidonoyl- sn-glycerol (SAG), and 1-stearoyl-2-linoleoyl- sn-glycerol (SLG) all augment NSCC activity. The effects of IP3 and OAG are fully abolished by lentiviral short-hairpin (sh)RNA-mediated TRPC3 channel knockdown (KD). The stimulatory effect of IP3 is eliminated by heparin, an IP3 receptor (IP3R) antagonist that blocks the IP3-binding site, but not by xestospongin C, the IP3R antagonist that has no effect on the IP3-binding site. Lentiviral shRNA-mediated KD of IP3R1, IP3R2, or IP3R3 does not alter the excitatory effect of IP3. TRPC3 channel KD greatly inhibits IP3-induced increase in intracellular Ca2+ concentration. IP3R1 KD produces a similar inhibitory effect. TRPC3 channel and IP3R1 KD both diminish the muscarinic receptor agonist methacholine-evoked Ca2+ responses. Taking these findings together, we conclude that IP3, the important intracellular second messenger, may activate TRPC3 channels to cause extracellular Ca2+ influx, in addition to opening IP3Rs to induce intracellular Ca2+ release. This novel extracellular Ca2+ entry route may play a significant role in mediating IP3-mediated numerous cellular responses in ASMCs and other cells.
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Pan, Sheng-Jun, Mingyan Zhu, Mohan K. Raizada, Colin Sumners, and Craig H. Gelband. "ANG II-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-α." American Journal of Physiology-Cell Physiology 281, no. 1 (July 1, 2001): C17—C23. http://dx.doi.org/10.1152/ajpcell.2001.281.1.c17.
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It was previously determined that ANG II and phorbol esters inhibit Kv current in neurons cultured from newborn rat hypothalamus and brain stem in a protein kinase C (PKC)- and Ca2+-dependent manner. Here, we have further defined this signaling pathway by investigating the roles of “physiological” activators of PKC and different PKC isozymes. The cell-permeable PKC activators, diacylglycerol (DAG) analogs 1,2-dioctanoyl- sn-glycerol (1 μmol/l, n = 7) and 1-oleoyl-2-acetyl- sn-glycerol (1 μmol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 μmol/l, n = 5) or by chelation of internal Ca2+ ( n = 8). PKC antisense (AS) oligodeoxynucleotides (2 μmol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-α-AS ( n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl- sn-glycerol on Kv current, whereas PKC-β-AS ( n = 4) and PKC-γ-AS ( n = 4) did not. These results suggest that the angiotensin type 1 receptor-mediated effects of ANG II on neuronal Kv current involve activation of PKC-α.
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Li, Liande, and Katherine A. Borkovich. "GPR-4 Is a Predicted G-Protein-Coupled Receptor Required for Carbon Source-Dependent Asexual Growth and Development in Neurospora crassa." Eukaryotic Cell 5, no. 8 (August 2006): 1287–300. http://dx.doi.org/10.1128/ec.00109-06.
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ABSTRACT The filamentous fungus Neurospora crassa is able to utilize a wide variety of carbon sources. Here, we examine the involvement of a predicted G-protein-coupled receptor (GPCR), GPR-4, during growth and development in the presence of different carbon sources in N. crassa. Δgpr-4 mutants have reduced mass accumulation compared to the wild type when cultured on high levels of glycerol, mannitol, or arabinose. The defect is most severe on glycerol and is cell density dependent. The genetic and physical relationship between GPR-4 and the three N. crassa Gα subunits (GNA-1, GNA-2, and GNA-3) was explored. All three Gα mutants are defective in mass accumulation when cultured on glycerol. However, the phenotypes of Δgna-1 and Δgpr-4 Δgna-1 mutants are identical, introduction of a constitutively activated gna-1 allele suppresses the defects of the Δgpr-4 mutation, and the carboxy terminus of GPR-4 interacts most strongly with GNA-1 in the yeast two-hybrid assay. Although steady-state cyclic AMP (cAMP) levels are normal in Δgpr-4 strains, exogenous cAMP partially remediates the dry mass defects of Δgpr-4 mutants on glycerol medium and Δgpr-4 strains lack the transient increase in cAMP levels observed in the wild type after addition of glucose to glycerol-grown liquid cultures. Our results support the hypothesis that GPR-4 is coupled to GNA-1 in a cAMP signaling pathway that regulates the response to carbon source in N. crassa. GPR-4-related GPCRs are present in the genomes of several filamentous ascomycete fungal pathogens, raising the possibility that a similar pathway regulates carbon sensing in these organisms.
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Kowalczyk-Bołtuć, Jolanta, Krzysztof Wiórkowski, and Jerzy Bełtowski. "Effect of Exogenous Hydrogen Sulfide and Polysulfide Donors on Insulin Sensitivity of the Adipose Tissue." Biomolecules 12, no. 5 (April 28, 2022): 646. http://dx.doi.org/10.3390/biom12050646.
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Hydrogen sulfide (H2S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in adipose tissue. We examined the effect of H2S and polysulfides on insulin sensitivity of the adipose tissue in rats. Plasma glucose, insulin, non-esterified fatty acids, and glycerol were measured after administration of H2S and the polysulfide donors, Na2S and Na2S4, respectively. In addition, the effect of Na2S and Na2S4 on insulin-induced glucose uptake and inhibition of lipolysis was studied in adipose tissue explants ex vivo. Na2S and Na2S4 administered in vivo at a single dose of 100 μmol/kg had no effect on plasma glucose and insulin concentrations. In addition, Na2S and Na2S4 did not modify the effect of insulin on plasma glucose, fatty acids, and glycerol concentrations. Na2S and Na2S4had no effect on the antilipolytic effect of insulin in adipose tissue explants ex vivo. The effect of insulin on 2-deoxyglucose uptake by adipose tissue was impaired in obese rats which was accompanied by lower insulin-induced tyrosine phosphorylation of IRS-1 and Akt. Na2S4, but not Na2S, improved insulin signaling and increased insulin-stimulated 2-deoxyglucose uptake by adipose tissue of obese rats. The results suggest that polysulfides may normalize insulin sensitivity, at least in the adipose tissue, in obesity/metabolic syndrome.
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Fricke, Katrin, Aleksandra Heitland, and Erik Maronde. "Cooperative Activation of Lipolysis by Protein Kinase A and Protein Kinase C Pathways in 3T3-L1 Adipocytes." Endocrinology 145, no. 11 (November 1, 2004): 4940–47. http://dx.doi.org/10.1210/en.2004-0803.
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Abstract In the present study, we investigate the coherence of signaling pathways leading to lipolysis in 3T3-L1 adipocytes. We observe two linear signaling pathways: one well known, acting via cAMP and protein kinase A (PKA) activation, and a second one induced by phorbol 12-myristate 13-acetate treatment involving protein kinase C (PKC) and MAPK. We demonstrate that both the PKA regulatory subunits RIα and RIIβ are expressed in 3T3-L1 adipocytes and are responsible for the lipolytic effect mediated via the cAMP/PKA pathway. Inhibition of the PKA pathway by the selective PKA inhibitor Rp-8-CPT-cAMPS does not impair lipolysis induced by PKC activation, and neither PD98059 nor U0126, as known MAPK kinase inhibitors, changes the level of glycerol release caused by PKA activation, indicating no cross-talk between these two pathways when only one is activated. However, when both are activated, they act synergistically on glycerol release. Additional experiments focusing on this synergy show no involvement of MAPK phosphorylation and cAMP formation. Phosphorylation of hormone-sensitive lipase is similar upon stimulation of either pathway, but we demonstrate a difference in the ability of both PKA and the PKC pathway activation to phosphorylate perilipin, which in turn may be an explanation for the different maximal lipolytic effect of both pathways.
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Hoy, Andrew J., Amanda E. Brandon, Nigel Turner, Matthew J. Watt, Clinton R. Bruce, Gregory J. Cooney, and Edward W. Kraegen. "Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation." American Journal of Physiology-Endocrinology and Metabolism 297, no. 1 (July 2009): E67—E75. http://dx.doi.org/10.1152/ajpendo.90945.2008.
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Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (∼300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.
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Shimizu, Maria Heloisa Massola, Rildo Aparecido Volpini, Ana Carolina de Bragança, Mariana Moura Nascimento, Desiree Rita Denelle Bernardo, Antonio Carlos Seguro, and Daniele Canale. "Administration of a single dose of lithium ameliorates rhabdomyolysis-associated acute kidney injury in rats." PLOS ONE 18, no. 2 (February 16, 2023): e0281679. http://dx.doi.org/10.1371/journal.pone.0281679.
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Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3β (GSK3β) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3β, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3β protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3β and possibly associated with a decrease in muscle injury.
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Son, Dajeong, and Myoungsook Lee. "DNAJC6 Gene Depressed Adipogenesis and Insulin Signaling in 3T3-L1 Cells." Current Developments in Nutrition 6, Supplement_1 (June 2022): 1086. http://dx.doi.org/10.1093/cdn/nzac070.045.
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Abstract Objectives Resting metabolic rate (RMR) accounts for 60–70% of total daily energy expenditure, and it is essential for establishing energy balance to prevent obesity. In a previous Genome-Wide Association Study (GWAS) for childhood obesity, we found the DNAJC6 gene as one of the genes that affected obesity prevalence to control energy expenditure with RMR. Since the mechanisms of the DNAJC6 gene on obesity are not clear, we performed adipogenesis, inflammatory adipokines, insulin resistance, and mitochondrial function to confirm dysfunction of energy balance using DNAJC6-overexpressed 3T3-L1 cells. Methods Compared to the control, the gene expression in DNAJC6-overexpressed was confirmed by MTT, RT-PCR, and western blotting. Adipogenesis and lipolysis were confirmed by ORO staining, the levels of triglyceride & free glycerol in medium, and western blotting for protein expression related to adipokines, insulin resistance, and mitochondrial function. Results DNAJC6-overexpressed significantly depressed adipogenesis (PPARγ, C/EBPα, aP2) and adipokines (LEPR, adiponectin, leptin) compared to the control, and it sequentially inhibited the insulin-GLUT4 signal factors (insulin receptor β, IRS-1, Akt (T308), AS160, GLUT4). As a result of ORO staining, it significantly inhibited adipocyte formation compared to the control. The levels of triglyceride & free glycerol in the medium were gradually increased in the control group, but not in DNAJC6-overexpressed, and DNAJC6-overexpressed inhibited lipolysis factor (HSL). UCP1, a mitochondrial thermogenesis marker induced by PGC1α, was suppressed in both groups. Conclusions We found that when DNAJC6 was overexpressed in 3T3-L1 cells, lipid synthesis and degradation were inhibited. Moreover, the insulin signal from IRS to Akt, AS160, and GLUT4 was sequentially suppressed in DNAJC6-overexpressed, thereby inhibiting intracellular glucose influx. In addition, we found that mitochondrial thermogenesis was inhibited by DNAJC6-overexpressed. Based on these findings, further studies are needed to understand the mechanism of how adipocytes overexpressing the DNAJC6 gene interact with other organs to use energy. Funding Sources This work was supported by the National Research Foundation of Korea grant funded by the Korea Government (MSIT;2019R1A2C1008434).
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Venugopal, Srivathsa C., Bidisha Chanda, Lisa Vaillancourt, Aardra Kachroo, and Pradeep Kachroo. "The common metabolite glycerol-3-phosphate is a novel regulator of plant defense signaling." Plant Signaling & Behavior 4, no. 8 (August 2009): 746–49. http://dx.doi.org/10.4161/psb.4.8.9111.
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Uchigashima, Motokazu, Madoka Narushima, Masahiro Fukaya, Istven Katona, Masanobu Kano, and Masahiko Watanabe. "Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling in the striatum." Neuroscience Research 58 (January 2007): S75. http://dx.doi.org/10.1016/j.neures.2007.06.440.
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Xu, Weitong, Fengyue Zhu, Dengqiang Wang, Daqing Chen, Xinbin Duan, Mingdian Liu, and Dapeng Li. "Comparative Analysis of Metabolites between Different Altitude Schizothorax nukiangensis (Cyprinidae, Schizothoracine) on the Qinghai-Tibet Plateau in Nujiang River." Water 15, no. 2 (January 9, 2023): 284. http://dx.doi.org/10.3390/w15020284.
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In order to investigate the influence of the high-altitude aquatic environment on indigenous fish metabolites, metabolomics studies were applied in this study. Widespread throughout the main stem of the Nujiang River of Schizothorax nukiangensis, we established sampling sites at high (3890 m) and low (2100 m) altitudes and selected six S. nukiangensis at each location, each weighing approximately 150 g and looking healthy. Then, metabolomics analysis was performed to compare the various metabolites of the two groups. Low concentrations of amino acids, dipeptides, eicosapentaenoic acid, docosahexaenoic acid, pentadecanoic acid, Thioetheramide-PC, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, 1-Stearoyl-sn-glycerol-3-phosphocholine, 1-Myristoyl-sn-glycero-3-phosphocholine and 1-Palmitoyl-sn-glycero-3-phosphocholine, high concentrations in S-Methyl-5’-thioadenosine, creatine, D-mannose-6-phosphate, D-mannose-1-phosphate, oleic acid and myristoleic acid were found in high-altitude fish liver. These differentially accumulated metabolites were involved in oxidative stress, energy metabolism, carbohydrate metabolism and lipid metabolism. mTOR signaling pathway, apoptosis and lysosome were the KEGG pathways that were enriched between different groups to ensure energy supply and limit tissue damage of fish at high altitudes. All these results contributed to the understanding of the high-altitude adaptation of S. nukiangensis in the Nujiang River. Nicotine and methoprene, two organic pollutants, performed differently in fish at different altitudes. Overall, our findings advanced the fundamental understanding of fish responses to high-altitude environments, adaptive mechanisms and organic contaminants pollution in the Nujiang River.
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Guaragnella, Nicoletta, Gennaro Agrimi, Pasquale Scarcia, Clelia Suriano, Isabella Pisano, Antonella Bobba, Cristina Mazzoni, Luigi Palmieri, and Sergio Giannattasio. "RTG Signaling Sustains Mitochondrial Respiratory Capacity in HOG1-Dependent Osmoadaptation." Microorganisms 9, no. 9 (September 6, 2021): 1894. http://dx.doi.org/10.3390/microorganisms9091894.
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Mitochondrial RTG-dependent retrograde signaling, whose regulators have been characterized in Saccharomyces cerevisiae, plays a recognized role under various environmental stresses. Of special significance, the activity of the transcriptional complex Rtg1/3 has been shown to be modulated by Hog1, the master regulator of the high osmolarity glycerol pathway, in response to osmotic stress. The present work focuses on the role of RTG signaling in salt-induced osmotic stress and its interaction with HOG1. Wild-type and mutant cells, lacking HOG1 and/or RTG genes, are compared with respect to cell growth features, retrograde signaling activation and mitochondrial function in the presence and in the absence of high osmostress. We show that RTG2, the main upstream regulator of the RTG pathway, contributes to osmoadaptation in an HOG1-dependent manner and that, with RTG3, it is notably involved in a late phase of growth. Our data demonstrate that impairment of RTG signaling causes a decrease in mitochondrial respiratory capacity exclusively under osmostress. Overall, these results suggest that HOG1 and the RTG pathway may interact sequentially in the stress signaling cascade and that the RTG pathway may play a role in inter-organellar metabolic communication for osmoadaptation.
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Tsukahara, Tamotsu. "PPARγNetworks in Cell Signaling: Update and Impact of Cyclic Phosphatidic Acid." Journal of Lipids 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/246597.
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Lysophospholipid (LPL) has long been recognized as a membrane phospholipid metabolite. Recently, however, the LPL has emerged as a candidate for diagnostic and pharmacological interest. LPLs include lysophosphatidic acid (LPA), alkyl glycerol phosphate (AGP), cyclic phosphatidic acid (cPA), and sphingosine-1-phosphate (S1P). These biologically active lipid mediators serve to promote a variety of responses that include cell proliferation, migration, and survival. These LPL-related responses are mediated by cell surface G-protein-coupled receptors and also intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). In this paper, we focus mainly on the most recent findings regarding the biological function of nuclear receptor-mediated lysophospholipid signaling in mammalian systems, specifically as they relate to health and diseases. Also, we will briefly review the biology of PPARγand then provide an update of lysophospholipids PPARγligands that are under investigation as a therapeutic compound and which are targets of PPARγrelevant to diseases.
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Tewson, Paul H., Scott Martinka, Nathan C. Shaner, Thomas E. Hughes, and Anne Marie Quinn. "New DAG and cAMP Sensors Optimized for Live-Cell Assays in Automated Laboratories." Journal of Biomolecular Screening 21, no. 3 (December 11, 2015): 298–305. http://dx.doi.org/10.1177/1087057115618608.
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Protein-based, fluorescent biosensors power basic research on cell signaling in health and disease, but their use in automated laboratories is limited. We have now created two live-cell assays, one for diacyl glycerol and another for cAMP, that are robust (Z′ > 0.7) and easily deployed on standard fluorescence plate readers. We describe the development of these assays, focusing on the parameters that were critical for optimization, in the hopes that the lessons learned can be generalized to the development of new biosensor-based assays.
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Salari, Hassan, Mervin Low, Sandra Howard, Glenn Edin, and Robert Bittman. "l-O-Hexadecyl-2-O-methyl-sn-glycero-3-phosphocholine inhibits diacylglycerol kinase in WEHI-3B cells." Biochemistry and Cell Biology 71, no. 1-2 (January 1, 1993): 36–42. http://dx.doi.org/10.1139/o93-006.
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The effects of 1-O-hexadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-16-OCH3-GPC) and its metabolite 1-O-hexadecyl-2-O-methyl-sn-glycerol (AMG) on the activity of diacylglycerol kinase (DGK) in WEHI-3B cells were investigated. Treatment of WEHI-3B cells with 200 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 5 min leads to the activation of cytosolic DGK without significant effect on microsomal DGK. When these cells were first exposed to 50 μM ET-16-OCH3-GPC for 30 min prior to activation with TPA, the activity of DGK was inhibited by about 70%, as measured by the ability of enzyme to form [32P]phosphatidic acid ([32P]PA). Addition of either ET-16-OCH3-GPC or AMG to the preparation of enzyme in vitro also inhibited 1,2-dioleoyl-sn-glycerol (DG) phosphorylation in the presence of [γ-32P]ATP. The IC50 value for inhibition of cytosolic DGK by ET-16-OCH3-GPC and AMG were about 8.5 and 15 μM, respectively. ET-16-OCH3-GPC also inhibited the ability of guanosine 5′-O-(3-thiophosphate) (GTP-7S) to activate DGK in vitro. The potency of ET-16-OCH3-GPC at 10 μM in inhibiting DGK was greater than that of sphingosine at 50 μM, but less than that of R59022 (a specific DGK inhibitor) at 10 μM. The abilities of ET-16-OCH3-GPC and AMG to inhibit cytosolic DGK in intact WEHI-3B cells and enzyme preparations in vitro suggest that the cytotoxic activity of ether lipids may in part result from interference with this vital enzyme involved in the synthesis of phospholipids from DG and in cell-signaling systems.Key words: diacylglycerol, kinases, second messengers, ether lipids, cancer, WEHI-3B cells.
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Zhang, Michael S., Aline Sandouk, and Jon C. D. Houtman. "Glycerol Monolaurate (GML) Inhibits Human T Cell Signaling, Metabolism, and Function By Disrupting Lipid Dynamics." Journal of Allergy and Clinical Immunology 139, no. 2 (February 2017): AB269. http://dx.doi.org/10.1016/j.jaci.2016.12.866.
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Shock, Teresa R., James Thompson, John R. Yates, and Hiten D. Madhani. "Hog1 Mitogen-Activated Protein Kinase (MAPK) Interrupts Signal Transduction between the Kss1 MAPK and the Tec1 Transcription Factor To Maintain Pathway Specificity." Eukaryotic Cell 8, no. 4 (February 13, 2009): 606–16. http://dx.doi.org/10.1128/ec.00005-09.
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ABSTRACT In Saccharomyces cerevisiae, the mating, filamentous growth (FG), and high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) signaling pathways share components and yet mediate distinct responses to different extracellular signals. Cross talk is suppressed between the mating and FG pathways because mating signaling induces the destruction of the FG transcription factor Tec1. We show here that HOG pathway activation results in phosphorylation of the FG MAPK, Kss1, and the MAPKK, Ste7. However, FG transcription is not activated because HOG signaling prevents the activation of Tec1. In contrast to the mating pathway, we find that the mechanism involves the inhibition of DNA binding by Tec1 rather than its destruction. We also find that nuclear accumulation of Tec1 is not affected by HOG signaling. Inhibition by Hog1 is apparently indirect since it does not require any of the consensus S/TP MAPK phosphorylation sites on Tec1, its DNA-binding partner Ste12, or the associated regulators Dig1 or Dig2. It also does not require the consensus MAPK sites of the Ste11 activator Ste50, in contrast to a recent proposal for a role for negative feedback in specificity. Our results demonstrate that HOG signaling interrupts the FG pathway signal transduction between the phosphorylation of Kss1 and the activation of DNA binding by Tec1.
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Bersching, Katharina, and Stefan Jacob. "The Molecular Mechanism of Fludioxonil Action Is Different to Osmotic Stress Sensing." Journal of Fungi 7, no. 5 (May 17, 2021): 393. http://dx.doi.org/10.3390/jof7050393.
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The group III two-component hybrid histidine kinase MoHik1p in the filamentous fungus Magnaporthe oryzae is known to be a sensor for external osmotic stress and essential for the fungicidal activity of the phenylpyrrole fludioxonil. The mode of action of fludioxonil has not yet been completely clarified but rather assumed to hyperactivate the high osmolarity glycerol (HOG) signaling pathway. To date, not much is known about the detailed molecular mechanism of how osmotic stress is detected or fungicidal activity is initiated within the HOG pathway. The molecular mechanism of signaling was studied using a mutant strain in which the HisKA signaling domain was modified by an amino acid change of histidine H736 to alanine A736. We found that MoHik1pH736A is as resistant to fludioxonil but not as sensitive to osmotic stress as the null mutant ∆Mohik1. H736 is required for fludioxonil action but is not essential for sensing sorbitol stress. Consequently, this report provides evidence of the difference in the molecular mechanism of fludioxonil action and the perception of osmotic stress. This is an excellent basis to understand the successful phenylpyrrole-fungicides’ mode of action better and will give new ideas to decipher cellular signaling mechanisms.
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Balsinde, Jesús, and María A. Balboa. "Plasmalogens in Innate Immune Cells: From Arachidonate Signaling to Ferroptosis." Biomolecules 14, no. 11 (November 18, 2024): 1461. http://dx.doi.org/10.3390/biom14111461.
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Polyunsaturated fatty acids such as arachidonic acid are indispensable components of innate immune signaling. Plasmalogens are glycerophospholipids with a vinyl ether bond in the sn-1 position of the glycerol backbone instead of the more common sn-1 ester bond present in “classical” glycerophospholipids. This kind of phospholipid is particularly rich in polyunsaturated fatty acids, especially arachidonic acid. In addition to or independently of the role of plasmalogens as major providers of free arachidonic acid for eicosanoid synthesis, plasmalogens also perform a varied number of functions. Membrane plasmalogen levels may determine parameters of the plasma membrane, such as fluidity and the formation of microdomains that are necessary for efficient signal transduction leading to optimal phagocytosis by macrophages. Also, plasmalogens may be instrumental for the execution of ferroptosis. This is a nonapoptotic form of cell death that is associated with oxidative stress. This review discusses recent data suggesting that, beyond their involvement in the cellular metabolism of arachidonic acid, the cells maintain stable pools of plasmalogens rich in polyunsaturated fatty acids for executing specific responses.
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Roeder, Amy D., Greg J. Hermann, Brian R. Keegan, Stephanie A. Thatcher, and Janet M. Shaw. "Mitochondrial Inheritance Is Delayed in Saccharomyces cerevisiae Cells Lacking the Serine/Threonine PhosphatasePTC1." Molecular Biology of the Cell 9, no. 4 (April 1998): 917–30. http://dx.doi.org/10.1091/mbc.9.4.917.
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In wild-type yeast mitochondrial inheritance occurs early in the cell cycle concomitant with bud emergence. Cells lacking thePTC1 gene initially produce buds without a mitochondrial compartment; however, these buds later receive part of the mitochondrial network from the mother cell. Thus, the loss ofPTC1 causes a delay, but not a complete block, in mitochondrial transport. PTC1 encodes a serine/threonine phosphatase in the high-osmolarity glycerol response (HOG) pathway. The mitochondrial inheritance delay in theptc1 mutant is not attributable to changes in intracellular glycerol concentrations or defects in the organization of the actin cytoskeleton. Moreover, epistasis experiments withptc1Δ and mutations in HOG pathway kinases reveal thatPTC1 is not acting through the HOG pathway to control the timing of mitochondrial inheritance. Instead, PTC1may be acting either directly or through a different signaling pathway to affect the mitochondrial transport machinery in the cell. These studies indicate that the timing of mitochondrial transport in wild-type cells is genetically controlled and provide new evidence that mitochondrial inheritance does not depend on a physical link between the mitochondrial network and the incipient bud site.
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Muratsu, Jun, Fumihiro Sanada, Nobutaka Koibuchi, Kana Shibata, Naruto Katsuragi, Shoji Ikebe, Yasuo Tsunetoshi, Hiromi Rakugi, Ryuichi Morishita, and Yoshiaki Taniyama. "Blocking Periostin Prevented Development of Inflammation in Rhabdomyolysis-Induced Acute Kidney Injury Mice Model." Cells 11, no. 21 (October 27, 2022): 3388. http://dx.doi.org/10.3390/cells11213388.
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Background: Rhabdomyolysis is the collapse of damaged skeletal muscle and the leakage of muscle-cell contents, such as electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation. The glomeruli filtered these products, leading to acute kidney injury (AKI) through several mechanisms, such as intratubular obstruction secondary to protein precipitation. The prognosis is highly mutable and depends on the underlying complications and etiologies. New therapeutic plans to reduce AKI are now needed. Up to now, several cellular pathways, with the nuclear factor kappa beta (NF-kB), as well as the proinflammatory effects on epithelial and tubular epithelial cells, have been recognized as the major pathway for the initiation of the matrix-producing cells in AKI. Recently, it has been mentioned that periostin (POSTN), an extracellular matrix protein, is involved in the development of inflammation through the modulation of the NF-kB pathway. However, how POSTN develops the inflammation protection in AKI by rhabdomyolysis is uncertain. This study aimed to investigate the role of POSTN in a rhabdomyolysis mice model of AKI induced by an intramuscular injection of 50% glycerol. Methods: In vivo, we performed an intramuscular injection of 50% glycerol (5 mg/kg body weight) to make rhabdomyolysis-induced AKI. We examined the expression level of POSTN through the progression of AKI after glycerol intramuscular injection for C57BL/6J wildtype (WT) mice. We sacrificed mice at 72 h after glycerol injection. We made periostin-null mice to examine the role of POSTN in acute renal failure. The role of periostin was further examined through in vitro methods. The development of renal inflammation is linked with the NF-kB pathway. To examine the POSTN function, we administrated hemin (100 μM) on NIH-3T3 fibroblast cells, and the following signaling pathways were examined. Results: The expression of periostin was highly increased, peaking at about 72 h after glycerol injection. The expression of inflammation-associated mRNAs such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-a) and IL-6, and tubular injury score in H-E staining were more reduced in POSTN-null mice than WT mice at 72 h after glycerol injection. Conclusion: POSTN was highly expressed in the kidney through rhabdomyolysis and was a positive regulator of AKI. Targeting POSTN might propose a new therapeutic strategy against the development of acute renal failure.
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Muller, Tania, Laurent Demizieux, Stéphanie Troy-Fioramonti, Joseph Gresti, Jean-Paul Pais de Barros, Hélène Berger, Bruno Vergès, and Pascal Degrace. "Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue." American Journal of Physiology-Endocrinology and Metabolism 313, no. 1 (July 1, 2017): E26—E36. http://dx.doi.org/10.1152/ajpendo.00374.2016.
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Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R−/− mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R−/−, suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the antilipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test if the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.
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Bailey, Lakiea J., Vivek Choudhary, and Wendy B. Bollag. "Possible Role of Phosphatidylglycerol-Activated Protein Kinase C-βII in Keratinocyte Differentiation." Open Dermatology Journal 11, no. 1 (October 24, 2017): 59–71. http://dx.doi.org/10.2174/1874372201711010059.
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Background: The epidermis is a continuously regenerating tissue maintained by a balance between proliferation and differentiation, with imbalances resulting in skin disease. We have previously found that in mouse keratinocytes, the lipid-metabolizing enzyme phospholipase D2 (PLD2) is associated with the aquaglyceroporin, aquaporin 3 (AQP3), an efficient transporter of glycerol. Our results also show that the functional interaction of AQP3 and PLD2 results in increased levels of phosphatidylglycerol (PG) in response to an elevated extracellular calcium level, which triggers keratinocyte differentiation. Indeed, we showed that directly applying PG can promote keratinocyte differentiation. Objective: We hypothesized that the differentiative effects of this PLD2/AQP3/PG signaling cascade, in which AQP3 mediates the transport of glycerol into keratinocytes followed by its PLD2-catalyzed conversion to PG, are mediated by protein kinase CβII (PKCβII), which contains a PG-binding domain in its carboxy-terminus. Method: To test this hypothesis we used quantitative RT-PCR, western blotting and immunocytochemistry. Results: We first verified the presence of PKCβII mRNA and protein in mouse keratinocytes. Next, we found that autophosphorylated (activated) PKCβII was redistributed upon treatment of keratinocytes with PG. In the unstimulated state phosphoPKCβII was found in the cytosol and perinuclear area; treatment with PG resulted in enhanced phosphoPKCβII localization in the perinuclear area. PG also induced translocation of phosphoPKCβII to the plasma membrane. In addition, we observed that overexpression of PKCβII enhanced calcium- and PG-induced keratinocyte differentiation without affecting calcium-inhibited keratinocyte proliferation. Conclusion: These results suggest that the PG produced by the PLD2/AQP3 signaling module may function by activating PKCβII.
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Lee, Mi Rim, Ji Eun Kim, Jun Young Choi, Jin Ju Park, Hye Ryeong Kim, Bo Ram Song, Ji Won Park, et al. "Morusin Functions as a Lipogenesis Inhibitor as Well as a Lipolysis Stimulator in Differentiated 3T3-L1 and Primary Adipocytes." Molecules 23, no. 8 (August 10, 2018): 2004. http://dx.doi.org/10.3390/molecules23082004.
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Conflicting results for morusin activity during adipogenic differentiation are reported in 3T3-L1 adipocytes and cancer cells. To elucidate the influence of morusin on fat metabolism, their anti-obesity effects and molecular mechanism were investigated in 3T3-L1 cells and primary adipocytes. Morusin at a dose of less than 20 µM does not induce any significant change in the viability of 3T3-L1 adipocytes. The accumulation of intracellular lipid droplets in 3T3-L1 adipocytes stimulated with 0.5 mM 3-isobutyl-1-methylxanthine, 1 µM dexamethasone, 10 µg/mL insulin in DMEM containing 10% FBS (MDI)-significantly reduces in a dose-dependent manner after morusin treatment. The phosphorylation level of members in the MAP kinase signaling pathway under the insulin receptor downstream also decrease significantly in the MDI + morusin-treated group compared to MDI + vehicle-treated group. Also, the expression of adipogenic transcription factors (PPARγ and C/EBPα) and lipogenic proteins (aP2 and FAS) are significantly attenuated by exposure to the compound in MDI-stimulated 3T3-L1 adipocytes. Furthermore, the decrease in the G0/G1 arrest of cell cycle after culturing in MDI medium was dramatically recovered after co-culturing in MDI + 20 µM morusin. Moreover, morusin treatment induces glycerol release in the primary adipocytes of SD rats and enhances lipolytic protein expression (HSL, ATGL, and perilipin) in differentiated 3T3-L1 adipocytes. Overall, the results of the present study provide strong evidence that morusin inhibits adipogenesis by regulating the insulin receptor signaling, cell cycle and adipogenic protein expression as well as stimulating lipolysis by enhancing glycerol release and lipolytic proteins expression.
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Ross, Sarah E., Robin L. Erickson, Isabelle Gerin, Paul M. DeRose, Laszlo Bajnok, Kenneth A. Longo, David E. Misek, et al. "Microarray Analyses during Adipogenesis: Understanding the Effects of Wnt Signaling on Adipogenesis and the Roles of Liver X Receptor α in Adipocyte Metabolism." Molecular and Cellular Biology 22, no. 16 (August 15, 2002): 5989–99. http://dx.doi.org/10.1128/mcb.22.16.5989-5999.2002.
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ABSTRACT Wnt signaling maintains preadipocytes in an undifferentiated state. When Wnt signaling is enforced, 3T3-L1 preadipocytes no longer undergo adipocyte conversion in response to adipogenic medium. Here we used microarray analyses to identify subsets of genes whose expression is aberrant when differentiation is blocked through enforced Wnt signaling. Furthermore, we used the microarray data to identify potentially important adipocyte genes and chose one of these, the liver X receptor α (LXRα), for further analyses. Our studies indicate that enforced Wnt signaling blunts the changes in gene expression that correspond to mitotic clonal expansion, suggesting that Wnt signaling inhibits adipogenesis in part through dysregulation of the cell cycle. Experiments designed to uncover the potential role of LXRα in adipogenesis revealed that this transcription factor, unlike CCAAT/enhancer binding protein α and peroxisome proliferator-activated receptor gamma, is not adipogenic but rather inhibits adipogenesis if inappropriately expressed and activated. However, LXRα has several important roles in adipocyte function. Our studies show that this nuclear receptor increases basal glucose uptake and glycogen synthesis in 3T3-L1 adipocytes. In addition, LXRα increases cholesterol synthesis and release of nonesterified fatty acids. Finally, treatment of mice with an LXRα agonist results in increased serum levels of glycerol and nonesterified fatty acids, consistent with increased lipolysis within adipose tissue. These findings demonstrate new metabolic roles for LXRα and increase our understanding of adipogenesis.
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Adhikari, Hema, and Paul J. Cullen. "Role of Phosphatidylinositol Phosphate Signaling in the Regulation of the Filamentous-Growth Mitogen-Activated Protein Kinase Pathway." Eukaryotic Cell 14, no. 4 (February 27, 2015): 427–40. http://dx.doi.org/10.1128/ec.00013-15.
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ABSTRACTReversible phosphorylation of the phospholipid phosphatidylinositol (PI) is a key event in the determination of organelle identity and an underlying regulatory feature in many biological processes. Here, we investigated the role of PI signaling in the regulation of the mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. Lipid kinases that generate phosphatidylinositol 4-phosphate [PI(4)P] at the Golgi (Pik1p) or PI(4,5)P2 at the plasma membrane (PM) (Mss4p and Stt4p) were required for filamentous-growth MAPK pathway signaling. Introduction of a conditional allele ofPIK1(pik1-83) into the filamentous (Σ1278b) background reduced MAPK activity and caused defects in invasive growth and biofilm/mat formation. MAPK regulatory proteins that function at the PM, including Msb2p, Sho1p, and Cdc42p, were mislocalized in thepik1-83mutant, which may account for the signaling defects of the PI(4)P kinase mutants. Other PI kinases (Fab1p and Vps34p), and combinations of PIP (synaptojanin-type) phosphatases, also influenced the filamentous-growth MAPK pathway. Loss of these proteins caused defects in cell polarity, which may underlie the MAPK signaling defect seen in these mutants. In line with this possibility, disruption of the actin cytoskeleton by latrunculin A (LatA) dampened the filamentous-growth pathway. Various PIP signaling mutants were also defective for axial budding in haploid cells, cell wall construction, or proper regulation of the high-osmolarity glycerol response (HOG) pathway. Altogether, the study extends the roles of PI signaling to a differentiation MAPK pathway and other cellular processes.
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Iyer, Prajish, Brian Jiang, Girish Venkataraman, Joo Y. Song, Wing Chung Chan, Tanya Siddiqi, Steven T. Rosen, Alexey Danilov, Antje Gohla, and Lili Wang. "Integrating Metabolomics and Molecular Pathways to Uncover Therapeutic Vulnerabilities in Richter's Transformation." Blood 144, Supplement 1 (November 5, 2024): 760. https://doi.org/10.1182/blood-2024-199843.
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Despite advances in targeted therapies, the aggressive transition of chronic lymphocytic leukemia (CLL) to Richter's transformation (RT) remains an unmet clinical need. While oxidative phosphorylation (OXPHOS) shaped by B-cell receptor signaling is a recognized feature in CLL and RT, metabolism changes driving RT progression are poorly understood. We recently developed an RT murine model by B-cell-restricted knockout of Mga, a negative regulator of MYC, in LSK cells derived from Cd19Cre-Cas9-del(13q)-Sf3b1-K700E mice. Murine RT cells exhibit high MYC and Ki67 expression, upregulated Mga targets Myc, Nme1 (Nucleoside diphosphate kinase), and elevated OXPHOS and lipid accumulation. Targeting MYC and OXPHOS with CDK9i-inhibitor (AZ5576) and OXPHOS complex IIi (TTFA- Triflurothenoylacetone) significantly improved overall survival in murine RT, highlighting the Mga-Myc-Nme1 axis and OXPHOS as viable targets in Mga KO-driven RT (Iyer et al., Sci. Transl. Med, 2024, Iyer et al, ASH, 2023). To delineate the metabolite changes from CLL to RT, we performed untargeted metabolomics profiling using murine CLL and RT cells. Our results revealed that fatty acid intermediates, glycerol-3P (Gro3P) (FC=11.7) and carnitine (FC=4.3), were significantly (p<0.01) elevated in RT cells. This is coupled with increased expression of the regulatory enzyme Pgp (phosphoglycolate phosphatase) in both murine and human RT samples, suggesting a potential role of MGA deletion in driving aberrant glycerolipid metabolism in RT. Given the heightened lipid accumulation and OXPHOS dependency in RT cells, we hypothesized that linking these metabolic pathways would unveil new vulnerabilities and therapeutic targets for this aggressive disease. To translate murine findings to human disease and define the molecular regulation for the metabolic changes, we performed untargeted metabolomics in human B cell lines (Nalm6, MEC1) with or without MGA KO. Fatty acid intermediates, Gro3P (FC=3.5), carnitine (FC=22.1), glutathione (g-glu-cys, FC=2.8), and the pentose phosphate pathway (IMP, FC=4.9; Glucuronic acid FC=4.4), were all significantly upregulated in MGA KO Nalm6 cells. Glycerolipid metabolism pathway was highly correlated (r=0.51, p=0.02) in MEC1 and Nalm6 cells with MGA deletion. Moreover, MGA KO cells showed decreased maximal respiration when treated with etomoxir, a fatty-acid oxidation inhibitor, indicating their reliance on lipid substrates. Further analysis using a labeled 13C-glucose-based isotope tracing assay revealed that MGA KO Nalm6 cells displayed an increased labeling of TCA cycle substrate citrate (FC=12 vs. 2.6, p < 0.001) and a higher labeled fraction of Gro3P (FC=59.4 vs. 36.3, p < 0.01) compared to control cells, highlighting a strong connection between the TCA cycle and glycerol metabolism upon MGA deletion. Gro3P is a key metabolite linking glycolysis, glycerolipid synthesis, and OXPHOS via the mitochondrial electron transfer shuttle. To delineate the role of Gro3P in linking the TCA cycle and glycerol metabolism in MGA KO, we examined its impact on lipid synthesis and OXPHOS. Treatment of MGA KO cell lines (MEC1) with Gro3P (500μM) increased lipid droplet formation, elevated the NADH/NAD+ ratio, and enhanced the expression of MYC, NME1, PGP, and mTOR signaling, indicating Gro3P as a critical regulator for lipid metabolism and OXPHOS via the MGA-MYC-NME1-PGP axis. As PGP is a known enzyme converting excessive detrimental Gro3P to less harmful glycerol, we overexpressed PGP in MEC1 cells to examine its role in mediating the crosstalk between OXPHOS and lipid metabolism. Overexpression of PGP increased glycerol levels and lipid accumulation, elevated oxygen consumption, and activated mTOR signaling, confirming PGP as a metabolic gene target. Given the availability of the PGP inhibitor CP1, we examined the therapeutic benefits of combining CP1 with the mitochondrial OXPHOS complex II inhibitor TTFA on murine RT in vivo. The combination improved overall survival (n=8 per group, p < 0.0001) compared to single treatments by reducing mTOR signaling, MYC, and NME1, highlighting the importance of concurrently targeting mitochondrial OXPHOS and glycerolipid metabolism in RT treatment. Our studies reveal Gro3P as a metabolite driver of OXPHOS in MGA KO RT via the Mga-Myc-Nme1-Pgp axis. Combining glycerolipid metabolism and OXPHOS targeting may offer effective strategies to conquer RT.
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Baranwal, Shivani, Gajendra Kumar Azad, Vikash Singh, and Raghuvir S. Tomar. "Signaling of Chloroquine-Induced Stress in the Yeast Saccharomyces cerevisiae Requires the Hog1 and Slt2 Mitogen-Activated Protein Kinase Pathways." Antimicrobial Agents and Chemotherapy 58, no. 9 (July 14, 2014): 5552–66. http://dx.doi.org/10.1128/aac.02393-13.
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ABSTRACTChloroquine (CQ) has been under clinical use for several decades, and yet little is known about CQ sensing and signaling mechanisms or about their impact on various biological pathways. We employed the budding yeastSaccharomyces cerevisiaeas a model organism to study the pathways targeted by CQ. Our screening with yeast mutants revealed that it targets histone proteins and histone deacetylases (HDACs). Here, we also describe the novel role of mitogen-activated protein kinases Hog1 and Slt2, which aid in survival in the presence of CQ. Cells deficient in Hog1 or Slt2 are found to be CQ hypersensitive, and both proteins were phosphorylated in response to CQ exposure. CQ-activated Hog1p is translocated to the nucleus and facilitates the expression of GPD1 (glycerol-3-phosphate dehydrogenase), which is required for the synthesis of glycerol (one of the major osmolytes). Moreover, cells treated with CQ exhibited an increase in intracellular reactive oxygen species (ROS) levels and the effects were rescued by addition of reduced glutathione to the medium. The deletion of SOD1, the superoxide dismutase in yeast, resulted in hypersensitivity to CQ. We have also observed P38 as well as P42/44 phosphorylation in HEK293T human cells upon exposure to CQ, indicating that the kinds of responses generated in yeast and human cells are similar. In summary, our findings define the multiple biological pathways targeted by CQ that might be useful for understanding the toxicity modulated by this pharmacologically important molecule.
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Reiser, Vladimír, Katharine E. D’Aquino, Ly-Sha Ee, and Angelika Amon. "The Stress-activated Mitogen-activated Protein Kinase Signaling Cascade Promotes Exit from Mitosis." Molecular Biology of the Cell 17, no. 7 (July 2006): 3136–46. http://dx.doi.org/10.1091/mbc.e05-12-1102.
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In budding yeast, a signaling network known as the mitotic exit network (MEN) triggers exit from mitosis. We find that hypertonic stress allows MEN mutants to exit from mitosis in a manner dependent on the high osmolarity glycerol (HOG) mitogen-activated protein (MAP) kinase cascade. The HOG pathway drives exit from mitosis in MEN mutants by promoting the activation of the MEN effector, the protein phosphatase Cdc14. Activation of Cdc14 depends on the Cdc14 early anaphase release network, a group of proteins that functions in parallel to the MEN to promote Cdc14 function. Notably, exit from mitosis is promoted by the signaling branch defined by the Sho1 osmosensing system, but not by the Sln1 osmosensor of the HOG pathway. Our results suggest that the stress MAP kinase pathway mobilizes programs to promote completion of the cell cycle and entry into G1 under unfavorable conditions.
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Johnson, Ali CM, Kirsten Becker, and Richard A. Zager. "Parenteral iron formulations differentially affect MCP-1, HO-1, and NGAL gene expression and renal responses to injury." American Journal of Physiology-Renal Physiology 299, no. 2 (August 2010): F426—F435. http://dx.doi.org/10.1152/ajprenal.00248.2010.
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Despite their prooxidant effects, ferric iron compounds are routinely administered to patients with renal disease to correct Fe deficiency. This study assessed relative degrees to which three clinically employed Fe formulations [Fe sucrose (FeS); Fe gluconate (FeG); ferumoxytol (FMX)] impact renal redox- sensitive signaling, cytotoxicity, and responses to superimposed stress [endotoxin; glycerol-induced acute renal failure (ARF)]. Cultured human proximal tubule (HK-2) cells, isolated proximal tubule segments (PTS), or mice were exposed to variable, but equal, amounts of FeS, FeG, or FMX. Oxidant-stimulated signaling was assessed by heme oxygenase-1 (HO-1) or monocyte chemoattractant protein (MCP)-1 mRNA induction. Cell injury was gauged by MTT assay (HK-2 cells), %LDH release (PTS), or renal cortical neutrophil gelatinase-associated lipoprotein (NGAL) protein/mRNA levels. Endotoxin sensitivity and ARF severity were assessed by TNF-α and blood urea nitrogen concentrations, respectively. FeS and FeG induced lethal cell injury (in HK-2 cells, PTS), increased HO-1 and MCP-1 mRNAs (HK-2 cells; in vivo), and markedly raised plasma (∼10 times), and renal cortical (∼3 times) NGAL protein levels. Both renal and extrarenal (e.g., hepatic) NGAL production likely contributed to these results, based on assessments of tissue and HK-2 cell NGAL mRNA. FeS pretreatment exacerbated endotoxemia. However, it conferred marked protection against the glycerol model of ARF (halving azotemia). FMX appeared to be “bioneutral,” as it exerted none of the above noted FeS/FeG effects. We conclude that 1) parenteral iron formulations that stimulate redox signaling can evoke cyto/nephrotoxicity; 2) secondary adaptive responses to this injury (e.g., HO-1/NGAL induction) can initiate a renal tubular cytoresistant state; this suggests a potential new clinical application for intravenous Fe therapy; and 3) FMX is bioneutral regarding these responses. The clinical implication(s) of the latter, vis a vis the treatment of Fe deficiency in renal disease patients, remains to be defined.
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Chen, Jianchun, Jian-Kang Chen, John R. Falck, Jagadeesh Setti Guthi, Siddam Anjaiah, Jorge H. Capdevila, and Raymond C. Harris. "Mitogenic Activity and Signaling Mechanism of 2-(14,15-Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate Metabolite." Molecular and Cellular Biology 27, no. 14 (July 15, 2007): 5260. http://dx.doi.org/10.1128/mcb.00920-07.
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Chen, Jianchun, Jian-Kang Chen, John R. Falck, Siddam Anjaiah, Jorge H. Capdevila, and Raymond C. Harris. "Mitogenic Activity and Signaling Mechanism of 2-(14,15- Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate Metabolite." Molecular and Cellular Biology 27, no. 8 (February 5, 2007): 3023–34. http://dx.doi.org/10.1128/mcb.01482-06.
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ABSTRACT Arachidonic acid is an essential constituent of cell membranes that is esterified to the sn-2 position of glycerophospholipids and is released from selected phospholipid pools by tightly regulated phospholipase cleavage. Metabolism of the released arachidonic acid by the cytochrome P450 enzyme system (cP450) generates biologically active compounds, including epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids. Here we report that 2-(14,15-epoxyeicosatrienoyl)glycerol (2-14,15-EG), a novel cP450 arachidonate metabolite produced in the kidney, is a potent mitogen for renal proximal tubule cells. This effect is mediated by activation of tumor necrosis factor alpha-converting enzyme (ADAM17), which cleaves membrane-bound transforming growth factor α (proTGF-α) and releases soluble TGF-α as a ligand that binds and activates epidermal growth factor receptor (EGFR). The present studies additionally demonstrate that the structurally related 14,15-EET stimulates release of soluble heparin-binding EGF-like growth factor as an EGFR ligand by activation of ADAM9, another member of the ADAM family. Thus, in addition to the characterization of 2-14,15-EG's mitogenic activity and signaling mechanism, our study provides the first example that two structurally related biologically active lipid mediators can activate different metalloproteinases and release different EGFR ligands in the same cell type to activate EGFR and stimulate cell proliferation.
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Rahib, Lola, Nicole K. MacLennan, Steve Horvath, James C. Liao, and Katrina M. Dipple. "Glycerol kinase deficiency alters expression of genes involved in lipid metabolism, carbohydrate metabolism, and insulin signaling." European Journal of Human Genetics 15, no. 6 (April 4, 2007): 646–57. http://dx.doi.org/10.1038/sj.ejhg.5201801.
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Sun, Shanfeng, Jiangzuo Luo, Hang Du, Guirong Liu, Manman Liu, Junjuan Wang, Shiwen Han, and Huilian Che. "Widely Targeted Lipidomics and Transcriptomics Analysis Revealed Changes of Lipid Metabolism in Spleen Dendritic Cells in Shrimp Allergy." Foods 11, no. 13 (June 25, 2022): 1882. http://dx.doi.org/10.3390/foods11131882.
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Shrimp allergy (SA) is pathological type 2 inflammatory immune responses against harmless shrimp protein allergen, which is caused by complex interactions between dendritic cells (DCs) and other immune cells. Lipid metabolism in different DCs states are significantly changed. However, the lipid metabolism of spleen DCs in SA remain ambiguous. In this study, we established a BALB/c mouse shrimp protein extract-induced allergy model to determine the lipid profile of spleen DCs in SA, and the molecular mechanism between lipid metabolism and immune inflammation was preliminarily studied. Spleen DCs were sorted by fluorescence-activated cell sorting, and then widely targeted lipidomics and transcriptomics analysis were performed. Principal component analysis presented the lipidome alterations in SA. The transcriptomic data showed that Prkcg was involved in lipid metabolism, immune system, and inflammatory signaling pathway. In the correlation analysis, the results suggested that Prkcg was positively correlated with triacylglycerol (Pearson correlation coefficient = 0.917, p = 0.01). The lipidomics and transcriptomics integrated pathway analysis indicated the activated metabolic conversion from triacylglycerol to 1,2-diacyl-sn-glycerol and the transmission of lipid metabolism to immune inflammation (from triacylglycerol and ceramide to Prkcg) in SA spleen DCs, and cellular experiments in vitro showed that glyceryl trioleate and C16 ceramide treatment induced immune function alteration in DCs.
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Rocha, Marina Campos, Camilla Alves Santos, and Iran Malavazi. "The Regulatory Function of the Molecular Chaperone Hsp90 in the Cell Wall Integrity of Pathogenic Fungi." Current Proteomics 16, no. 1 (November 23, 2018): 44–53. http://dx.doi.org/10.2174/1570164615666180820155807.
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Different signaling cascades including the Cell Wall Integrity (CWI), the High Osmolarity Glycerol (HOG) and the Ca2+/calcineurin pathways control the cell wall biosynthesis and remodeling in fungi. Pathogenic fungi, such as Aspergillus fumigatus and Candida albicans, greatly rely on these signaling circuits to cope with different sources of stress, including the cell wall stress evoked by antifungal drugs and the host’s response during infection. Hsp90 has been proposed as an important regulatory protein and an attractive target for antifungal therapy since it stabilizes major effector proteins that act in the CWI, HOG and Ca2+/calcineurin pathways. Data from the human pathogen C. albicans have provided solid evidence that loss-of-function of Hsp90 impairs the evolution of resistance to azoles and echinocandin drugs. In A. fumigatus, Hsp90 is also required for cell wall integrity maintenance, reinforcing a coordinated function of the CWI pathway and this essential molecular chaperone. In this review, we focus on the current information about how Hsp90 impacts the aforementioned signaling pathways and consequently the homeostasis and maintenance of the cell wall, highlighting this cellular event as a key mechanism underlying antifungal therapy based on Hsp90 inhibition.