scholarly journals Rewiring the Three-Carbon Metabolism Abrogates Multiple MAPK-Induced Cellular Dysfunctions During Metabolic Disorder

2021 ◽  
Author(s):  
Alexandre K Dube ◽  
Nicolas Malenfant ◽  
Florence Ladonne ◽  
Amanda Piano ◽  
Karamat Mohammad ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Model Organism ◽  
Mitogen Activated Protein Kinase ◽  
Dihydroxyacetone Phosphate ◽  
Membrane Raft ◽  
Glycerol Phosphate ◽  
Metabolic Dysregulation ◽  
Mitogen Activated Protein ◽  
Glycerol Phosphate Dehydrogenase ◽  
Sustained Activation

Loss of membrane raft integrity, metabolic dysregulation and inflammation are hallmarks of chronic diseases and aging. It is not well understood how the stress response itself may contribute to the manifestation of these common traits. To explore this question, we screened the model organism S. cerevisiae, for the secretion of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a proxy for membrane raft instability. It is shown here that the multiple cellular dysfunctions previously described for a defect in the methylation pathway for phosphatidyl choline (PC) synthesis (opi3Δ) are linked with GPI-APs secretion. They collectively result from the sustained activation of the mitogen-activated protein kinase (MAPK) Hog1p. Through modifying the dihydroxyacetone phosphate / glycerol-3-phosphate ratio, activated MAPK promotes phospholipid gene de-repression and interferes with GPI anchor synthesis. Rewiring the three carbon metabolism, namely by deleting the mitochondrial glycerol phosphate dehydrogenase, abrogated the opi3Δ mutant pleiotropic phenotypes identifying key targets to counteract MAPK-induced cellular dysfunctions.

scholarly journals Induction of S. cerevisiae Filamentous Differentiation by Slowed DNA Synthesis Involves Mec1, Rad53 and Swe1 Checkpoint Proteins

2003 ◽  
Vol 14 (12) ◽  
pp. 5116-5124 ◽  
Author(s):  
Yi Wei Jiang ◽  
Christopher Minkyu Kang
Keyword(s):  
Dna Synthesis ◽  
Nitrogen Starvation ◽  
Model Organism ◽  
Filamentous Growth ◽  
Mitogen Activated Protein Kinase ◽  
Cell Cycle Regulators ◽  
Checkpoint Proteins ◽  
The Core ◽  
Mitogen Activated Protein ◽  
Mitotic Cyclin

A key question in eukaryotic differentiation is whether there are common regulators or biochemical events that are required for diverse types of differentiation or whether there is a core mechanism for differentiation. The unicellular model organism Saccharomyces cerevisiae undergoes filamentous differentiation in response to environmental cues. Because conserved cell cycle regulators, the mitotic cyclin-dependent kinase Clb2/Cdc28, and its inhibitor Swe1 were found to be involved in both nitrogen starvation- and short chain alcohol-induced filamentous differentiation, they were identified as components of the core mechanism for filamentous differentiation. We report here that slowed DNA synthesis also induces yeast filamentous differentiation through conserved checkpoint proteins Mec1 and Rad53. Swe1 and Clb2 are also involved in this form of differentiation, and the core status of Swe1/Clb2/Cdc28 in the mechanism of filamentous differentiation has therefore been confirmed. Because the cAMP and filamentous growth mitogen-activated protein kinase pathways that mediate nitrogen starvation-induced filamentous differentiation are not required for slowed DNA synthesis-induced filamentous growth, they can therefore be excluded from the core mechanism. More significantly, slowed DNA synthesis also induces differentiation in mammalian cancer cells, and such stimulus conservation may indicate that the core mechanism for yeast filamentous differentiation is conserved in mammalian differentiation.

scholarly journals Met/Hepatocyte Growth Factor Receptor Ubiquitination Suppresses Transformation and Is Required for Hrs Phosphorylation

2005 ◽  
Vol 25 (21) ◽  
pp. 9632-9645 ◽  
Author(s):  
Jasmine V. Abella ◽  
Pascal Peschard ◽  
Monica A. Naujokas ◽  
Tong Lin ◽  
Caroline Saucier ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Endosomal Trafficking ◽  
Met Receptor ◽  
Down Regulation ◽  
Lysosomal Sorting ◽  
Mitogen Activated Protein ◽  
Sustained Activation

ABSTRACT The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity.

scholarly journals Menin Is a Regulator of the Stress Response in Drosophila melanogaster

2005 ◽  
Vol 25 (22) ◽  
pp. 9960-9972 ◽  
Author(s):  
Maria Papaconstantinou ◽  
Ying Wu ◽  
Hendrik Nikolaas Pretorius ◽  
Nishi Singh ◽  
Gabriella Gianfelice ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Rna Interference ◽  
Stress Response ◽  
Heat Shock ◽  
Model Organism ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Control Of Gene Expression ◽  
Damage Sensing ◽  
Mitogen Activated Protein

ABSTRACT Menin, the product of the multiple endocrine neoplasia type I gene, has been implicated in several biological processes, including the control of gene expression and apoptosis, the modulation of mitogen-activated protein kinase pathways, and DNA damage sensing or repair. In this study, we have investigated the function of menin in the model organism Drosophila melanogaster. We show that Drosophila lines overexpressing menin or an RNA interference for this gene develop normally but are impaired in their response to several stresses, including heat shock, hypoxia, hyperosmolarity and oxidative stress. In the embryo subjected to heat shock, this impairment was characterized by a high degree of developmental arrest and lethality. The overexpression of menin enhanced the expression of HSP70 in embryos and interfered with its down-regulation during recovery at the normal temperature. In contrast, the inhibition of menin with RNA interference reduced the induction of HSP70 and blocked the activation of HSP23 upon heat shock, Menin was recruited to the Hsp70 promoter upon heat shock and menin overexpression stimulated the activity of this promoter in embryos. A 70-kDa inducible form of menin was expressed in response to heat shock, indicating that menin is also regulated in conditions of stress. The induction of HSP70 and HSP23 was markedly reduced or absent in mutant embryos harboring a deletion of the menin gene. These embryos, which did not express the heat shock-inducible form of menin, were also hypersensitive to various conditions of stress. These results suggest a novel role for menin in the control of the stress response and in processes associated with the maintenance of protein integrity.

scholarly journals Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes

2000 ◽  
Vol 350 (3) ◽  
pp. 891-899 ◽  
Author(s):  
Anu PUNN ◽  
James W. MOCKRIDGE ◽  
Saleha FAROOQUI ◽  
Michael S. MARBER ◽  
Richard J. HEADS
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
P38 Mapk ◽  
Cell Injury ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Sustained Activation

Delayed cytoprotection (preconditioning) occurs 24h after sublethal simulated ischaemia and reperfusion (SI/R) in neonatal rat ventricular cardiomyocytes. SI/R was used to investigate the role of activation of mitogen-activated protein kinases (MAPKs), stress-activated protein kinases (SAPKs) and phosphoinositide 3-kinase-dependent protein kinase B (PKB)/Akt in cytoprotection. SI resulted in transient dual (Thr/Tyr) phosphorylation of p42/p44-MAPK and p38-MAPK, weak phosphorylation of p46/p54-SAPK, but no phosphorylation of PKB. ‘Reperfusion’ caused further transient phosphorylation of p38-MAPK, but sustained phosphorylation of p42/p44-MAPK (lasting 4h) and of Ser473 of PKB (lasting 2h). Furthermore, SI/R (24h) induced delayed protection against lethal SI, as determined by an increase in cell viability {bioreduction of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide]} and a decrease in cell injury (release of creatine kinase). Both protection and phosphorylation of p42/p44-MAPK were blocked by the MEK-1/2 (MAPK/Erk kinase-1/2) inhibitor PD98059 (50µM) when given during SI/R, but not when given during SI alone. The p38-MAPK inhibitor SB203580 (10µM) blocked the p38-MAPK-dependent phosphorylation of activating transcription factor 2 in vitro, and the phosphoinositide 3-kinase inhibitor wortmannin (100nM) blocked PKB phosphorylation on Ser473. However, neither SB203580 nor wortmannin had any effect on delayed protection. Therefore sustained activation of p42/p44-MAPK during simulated ‘reperfusion’ following sublethal SI mediates preconditioning in cardiomyocytes independently of transient activation of p38-MAPK or sustained activation of PKB.

scholarly journals Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival

1997 ◽  
Vol 324 (2) ◽  
pp. 365-369 ◽  
Author(s):  
Frank J. GUNN-MOORE ◽  
Alan G. WILLIAMS ◽  
Nicholas J. TOMS ◽  
Jeremy M. TAVARÉ
Keyword(s):  
Map Kinase ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Cerebellar Granule ◽  
P70s6 Kinase ◽  
Mitogen Activated Protein ◽  
Sustained Activation

We have investigated the role of mitogen-activated protein (MAP) kinase in the survival of cerebellar granule cells in primary culture. Brain-derived neurotrophic factor (BDNF) and insulin, but not epidermal growth factor (EGF), promoted the survival of P6 cerebellar granule neurons. BDNF promoted a sustained activation of MAP kinase, whereas that induced by EGF was only transient. Insulin promoted a small but transient activation of MAP kinase that was completely blocked by PD98059, an inhibitor of MAP kinase kinase activation. PD98059 had no effect on the insulin- or BDNF-induced survival of cerebellar granule cells. We also investigated the role of p70S6 kinase in survival. The activation of p70S6 kinase by EGF was transient, whereas BDNF and insulin promoted a sustained activation of p70S6 kinase. Rapamycin, which blocked p70S6 kinase activation, had no effect on the BDNF- or insulin-induced survival of cerebellar granule cells. We conclude that sustained activation of MAP kinase is not correlated with the survival response of cerebellar granule cells; indeed insulin-mediated survival is independent of MAP kinase. Survival of cerebellar granule cells is also independent of the activation of p70S6 kinase.

scholarly journals Cellular signalling and the complexity of biological timing: insights from the ultradian clock of Schizosaccharomyces pombe

2001 ◽  
Vol 356 (1415) ◽  
pp. 1725-1733 ◽  
Author(s):  
Fred Kippert
Keyword(s):  
Protein Kinase ◽  
Schizosaccharomyces Pombe ◽  
Model Organism ◽  
Circadian Clocks ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Cellular Signalling ◽  
Short Period ◽  
Mitogen Activated Protein ◽  
Cellular Signalling Pathways

The molecular bases of circadian clocks are complex and cannot be sufficiently explained by the relatively simple feedback loops, based on transcription and translation, of current models. The existence of additional oscillators has been demonstrated experimentally, but their mechanism(s) have so far resisted elucidation and any universally conserved clock components have yet to be identified. The fission yeast, Schizosaccharomyces pombe , as a simple and well–characterized eukaryote, is a useful model organism in the investigation of many aspects of cell regulation. In fast–growing cells of the yeast an ultradian clock operates, which can serve as a model system to analyse clock complexity. This clock shares strict period homeostasis and efficient entrainment with circadian clocks but, because of its short period of 30 min, mechanisms other than a transcription/translation–based feedback loop must be working. An initial systematic screen involving over 200 deletion mutants has shown that major cellular signalling pathways (calcium/phosphoinositide, mitogen–activated protein kinase and cAMP/protein kinase A) are crucial for the normal functioning of this ultradian clock. A comparative examination of the role of cellular signalling pathways in the S.pombe ultradian clock and in the circadian timekeeping of different eukaryotes may indicate common principles in biological timing processes that are universally conserved amongst eukaryotes.

Chinese Medicine Induces Neurite Outgrowth in PC12 Mutant Cells Incapable of Differentiation

2002 ◽  
Vol 30 (02n03) ◽  
pp. 287-295 ◽  
Author(s):  
Yoshio Kano ◽  
Shinichiro Takaguchi ◽  
Tsutomu Nohno ◽  
Fukumi Hiragami ◽  
Kenji Kawamura ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Pc12 Cells ◽  
Mutant Cell ◽  
Mitogen Activated Protein Kinase ◽  
Chinese Medicines ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Mutant Cells ◽  
Stimulation Of ◽  
Sustained Activation

During continuous culture of neural PC12 cells, we obtained a drug-hypersensitive PC12 mutant cell that showed high stimulation of neurite outgrowth by various drugs. When several Chinese medicines such as Shu-Jing-Huo-Xie-Tang and Wu-Ling-San were provided to these PC12 mutant cells, the frequency of nerve growth factor (NGF)-induced neurite outgrowth increased approximately 30-fold compared to NGF alone. Neurite outgrowth induced by NGF in PC12 cells is accompanied by sustained activation of mitogen-activated protein kinase (MAPK); however, these Chinese medicines did not induce MAPK activity. The findings thus indicate that certain Chinese medicines may induce neurite outgrowth by a novel mechanism which is distinct from the NGF-activated pathway in PC12 mutant cells.

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