scholarly journals The neural circuit linking mushroom body parallel circuits induces memory consolidation in Drosophila

2019 ◽  
Vol 116 (32) ◽  
pp. 16080-16085 ◽  
Author(s):  
Hiroko Awata ◽  
Mai Takakura ◽  
Yoko Kimura ◽  
Ikuko Iwata ◽  
Tomoko Masuda ◽  
...  
Keyword(s):  
Memory Consolidation ◽  
Mushroom Body ◽  
Dopaminergic Neuron ◽  
Neural Circuit ◽  
Spacing Effect ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Parallel Circuits ◽  
Perk Expression ◽  
Mitogen Activated Protein

Memory consolidation is augmented by repeated learning following rest intervals, which is known as the spacing effect. Although the spacing effect has been associated with cumulative cellular responses in the neurons engaged in memory, here, we report the neural circuit-based mechanism for generating the spacing effect in the memory-related mushroom body (MB) parallel circuits in Drosophila. To investigate the neurons activated during the training, we monitored expression of phosphorylation of mitogen-activated protein kinase (MAPK), ERK [phosphorylation of extracellular signal-related kinase (pERK)]. In an olfactory spaced training paradigm, pERK expression in one of the parallel circuits, consisting of γm neurons, was progressively inhibited via dopamine. This inhibition resulted in reduced pERK expression in a postsynaptic GABAergic neuron that, in turn, led to an increase in pERK expression in a dopaminergic neuron specifically in the later session during spaced training, suggesting that disinhibition of the dopaminergic neuron occurs during spaced training. The dopaminergic neuron was significant for gene expression in the different MB parallel circuits consisting of α/βs neurons for memory consolidation. Our results suggest that the spacing effect-generating neurons and the neurons engaged in memory reside in the distinct MB parallel circuits and that the spacing effect can be a consequence of evolved neural circuit architecture.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

2008 ◽  
Vol 26 (13) ◽  
pp. 2139-2146 ◽  
Author(s):  
Alex A. Adjei ◽  
Roger B. Cohen ◽  
Wilbur Franklin ◽  
Clive Morris ◽  
David Wilson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phase Ii ◽  
Geometric Mean ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Type ◽  
Ki 67 ◽  
Phase Ii Studies ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

scholarly journals 15-deoxy-Δ12,14-prostaglandin J2Down-Regulates Activin-Induced Activin Receptor, Smad, and Cytokines Expression via Suppression of NF-κB and MAPK Signaling in HepG2 Cells

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Seung-Won Park ◽  
Chunghee Cho ◽  
Byung-Nam Cho ◽  
Youngchul Kim ◽  
Tae Won Goo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepg2 Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Activin A ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Regulatory Effects ◽  
Activin Receptors

15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) and activin are implicated in the control of apoptosis, cell proliferation, and inflammation in cells. We examined both the mechanism by which 15d-PGJ2regulates the transcription of activin-induced activin receptors (ActR) and Smads in HepG2 cells and the involvement of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in this regulation. Activin A (25 ng/mL) inhibited HepG2 cell proliferation, whereas 15d-PGJ2(2 μM and 5 μM) had no effect. Activin A and 15d-PGJ2showed different regulatory effects on ActR and Smad expression, NF-κB p65 activity and MEK/ERK phosphorylation, whereas they both decreased IL-6 production and increased IL-8 production. When co-stimulated with 15d-PGJ2and activin, 15d-PGJ2inhibited the activin-induced increases in ActR and Smad expression, and decreased activin-induced IL-6 production. However, it increased activin-induced IL-8 production. In addition, 15d-PGJ2inhibited activin-induced NF-κB p65 activity and activin-induced MEK/ERK phosphorylation. These results suggest that 15d-PGJ2suppresses activin-induced ActR and Smad expression, down-regulates IL-6 production, and up-regulates IL-8 production via suppression of NF-κB and MAPK signaling pathway in HepG2 cells. Regulation of ActR and Smad transcript expression and cytokine production involves NF-κB and the MAPK pathway via interaction with 15d-PGJ2/activin/Smad signaling.

scholarly journals MED1 Phosphorylation Promotes Its Association with Mediator: Implications for Nuclear Receptor Signaling

2008 ◽  
Vol 28 (12) ◽  
pp. 3932-3942 ◽  
Author(s):  
Madesh Belakavadi ◽  
Pradeep K. Pandey ◽  
Ravi Vijayvargia ◽  
Joseph D. Fondell
Keyword(s):  
Rna Polymerase Ii ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Broad Array ◽  
Mitogen Activated Protein

ABSTRACT Mediator is a conserved multisubunit complex that acts as a functional interface between regulatory transcription factors and the general RNA polymerase II initiation apparatus. MED1 is a pivotal component of the complex that binds to nuclear receptors and a broad array of other gene-specific activators. Paradoxically, MED1 is found in only a fraction of the total cellular Mediator complexes, and the mechanisms regulating its binding to the core complex remain unclear. Here, we report that phosphorylation of MED1 by mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) promotes its association with Mediator. We show that MED1 directly binds to the MED7 subunit and that ERK phosphorylation of MED1 enhances this interaction. Interestingly, we found that both thyroid and steroid hormones stimulate MED1 phosphorylation in vivo and that MED1 phosphorylation is required for its nuclear hormone receptor coactivator activity. Finally, we show that MED1 phosphorylation by ERK enhances thyroid hormone receptor-dependent transcription in vitro. Our findings suggest that ERK phosphorylation of MED1 is a regulatory mechanism that promotes MED1 association with Mediator and, as such, may facilitate a novel feed-forward action of nuclear hormones.

scholarly journals Endothelial nitric oxide synthase is regulated by ERK phosphorylation at Ser602

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
John C. Salerno ◽  
Dipak K. Ghosh ◽  
Raj Razdan ◽  
Katy A. Helms ◽  
Christopher C. Brown ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Binding Site ◽  
Endothelial Nitric Oxide Synthase ◽  
Mitogen Activated Protein Kinase ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

eNOS (endothelial nitric oxide synthase) contains a MAPK (mitogen-activated protein kinase)-binding site associated with a major eNOS control element. Purified ERK (extracellular-signal-regulated kinase) phosphorylates eNOS with a stoichiometry of 2–3 phosphates per eNOS monomer. Phosphorylation decreases NO synthesis and cytochrome c reductase activity. Three sites of phosphorylation were detected by MS. All sites matched the SP and TP MAPK (mitogen-activated protein kinase) phosphorylation motif. Ser602 lies at the N-terminal edge of the 42-residue eNOS AI (autoinhibitory) element. The pentabasic MAPK-binding site lies at the opposite end of the AI, and other critical regulatory features are between them. Thr46 and Ser58 are located in a flexible region associated with the N terminus of the oxygenase domain. In contrast with PKC (protein kinase C), phosphorylation by ERK did not significantly interfere with CaM (calmodulin) binding as analysed by optical biosensing. Instead, ERK phosphorylation favours a state in which FMN and FAD are in close association and prevents conformational changes that expose reduced FMN to acceptors. The close associations between control sites in a few regions of the molecule suggest that control of signal generation is modulated by multiple inputs interacting directly on the surface of eNOS via overlapping binding domains and tightly grouped targets.

scholarly journals Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development

2008 ◽  
Vol 180 (5) ◽  
pp. 947-955 ◽  
Author(s):  
Gergana Galabova-Kovacs ◽  
Federica Catalanotti ◽  
Dana Matzen ◽  
Gloria X. Reyes ◽  
Jürgen Zezula ◽  
...  
Keyword(s):  
System Development ◽  
Genetic Disorders ◽  
Nervous System Development ◽  
Mitogen Activated Protein Kinase ◽  
Oligodendrocyte Differentiation ◽  
Erk Phosphorylation ◽  
Kinase Suppressor Of Ras ◽  
Mitogen Activated Protein ◽  
Neuronal Precursors

Mutations in the extracellular signal-regulated kinase (ERK) pathway, particularly in the mitogen-activated protein kinase/ERK kinase (MEK) activator B-Raf, are associated with human tumorigenesis and genetic disorders. Hence, B-Raf is a prime target for molecule-based therapies, and understanding its essential biological functions is crucial for their success. B-Raf is expressed preferentially in cells of neuronal origin. Here, we show that in mice, conditional ablation of B-Raf in neuronal precursors leads to severe dysmyelination, defective oligodendrocyte differentiation, and reduced ERK activation in brain. Both B-Raf ablation and chemical inhibition of MEK impair oligodendrocyte differentiation in vitro. In glial cell cultures, we find B-Raf in a complex with MEK, Raf-1, and kinase suppressor of Ras. In B-Raf–deficient cells, more Raf-1 is recruited to MEK, yet MEK/ERK phosphorylation is impaired. These data define B-Raf as the rate-limiting MEK/ERK activator in oligodendrocyte differentiation and myelination and have implications for the design and use of Raf inhibitors.

scholarly journals Regulation and functional consequences of ADP receptor-mediated ERK2 activation in platelets

2007 ◽  
Vol 404 (2) ◽  
pp. 299-308 ◽  
Author(s):  
Analia Garcia ◽  
Haripriya Shankar ◽  
Swaminathan Murugappan ◽  
Soochong Kim ◽  
Satya P. Kunapuli
Keyword(s):  
Thromboxane A2 ◽  
Underlying Mechanism ◽  
P2y Receptors ◽  
Extracellular Calcium ◽  
Mitogen Activated Protein Kinase ◽  
Erk Activation ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Adp Receptor

We have previously shown that ADP-induced thromboxane generation in platelets requires signalling events from the Gq-coupled P2Y1 receptor (platelet ADP receptor coupled to stimulation of phospholipase C) and the Gi-coupled P2Y12 receptor (platelet ADP receptor coupled to inhibition of adenylate cyclase) in addition to outside-in signalling. While it is also known that extracellular calcium negatively regulates ADP-induced thromboxane A2 generation, the underlying mechanism remains unclear. In the present study we sought to elucidate the signalling mechanisms and regulation by extracellular calcium of ADP-induced thromboxane A2 generation in platelets. ERK (extracllular-signal-regulated kinase) 2 activation occurred when outside-in signalling was blocked, indicating that it is a downstream event from the P2Y receptors. However, blockade of either P2Y1 or the P2Y12 receptors with corresponding antagonists completely abolished ERK phosphorylation, indicating that both P2Y receptors are required for ADP-induced ERK activation. Inhibitors of Src family kinases or the ERK upstream kinase MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] abrogated ADP-induced ERK phosphorylation and thromboxane A2 generation. Finally ADP- or Gi+Gz-induced ERK phosphorylation was blocked in the presence of extracellular calcium. The present studies show that ERK2 is activated downstream of P2Y receptors through a complex mechanism involving Src kinases and this plays an important role in ADP-induced thromboxane A2 generation. We also conclude that extracellular calcium blocks ADP-induced thromboxane A2 generation through the inhibition of ERK activation.

scholarly journals Extracellular Signal-Regulated Kinase Promotes Rho-Dependent Focal Adhesion Formation by Suppressing p190A RhoGAP

2010 ◽  
Vol 30 (13) ◽  
pp. 3233-3248 ◽  
Author(s):  
Ashok K. Pullikuth ◽  
Andrew D. Catling
Keyword(s):  
Adhesion Formation ◽  
Rho Kinase ◽  
Focal Adhesions ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Phosphorylation ◽  
C Terminus ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Cell migration is critical for normal development and for pathological processes including cancer cell metastasis. Dynamic remodeling of focal adhesions and the actin cytoskeleton are crucial determinants of cell motility. The Rho family and the mitogen-activated protein kinase (MAPK) module consisting of MEK-extracellular signal-regulated kinase (ERK) are important regulators of these processes, but mechanisms for the integration of these signals during spreading and motility are incompletely understood. Here we show that ERK activity is required for fibronectin-stimulated Rho-GTP loading, Rho-kinase function, and the maturation of focal adhesions in spreading cells. We identify p190A RhoGAP as a major target for ERK signaling in adhesion assembly and identify roles for ERK phosphorylation of the C terminus in p190A localization and activity. These observations reveal a novel role for ERK signaling in adhesion assembly in addition to its established role in adhesion disassembly.

scholarly journals Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition

2010 ◽  
Vol 118 (12) ◽  
pp. 727-736 ◽  
Author(s):  
Elias N. Glaros ◽  
Woojin S. Kim ◽  
Brett Garner
Keyword(s):  
Kinase Inhibitor ◽  
Density Lipoprotein ◽  
Mitogen Activated Protein Kinase ◽  
Serine Palmitoyltransferase ◽  
Protein Levels ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Primary Mouse ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate

Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 μM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway.

Involvement of the Mitogen-activated Protein Kinase Family in Tetracaine-induced PC12 Cell Death

2002 ◽  
Vol 96 (5) ◽  
pp. 1191-1201 ◽  
Author(s):  
Zhiming Tan ◽  
Shuji Dohi ◽  
Jinen Chen ◽  
Yosiko Banno ◽  
Yoshinori Nozawa
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Pc12 Cells ◽  
Dna Fragmentation ◽  
Local Anesthetics ◽  
Caspase 3 ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Erk Phosphorylation ◽  
Mitogen Activated Protein

Background To explore whether cytotoxicity of local anesthetics is related to apoptosis, the authors examined how local anesthetics affect mitogen-activated protein kinase (MAPK) family members, extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs)-stress-activated protein kinases, and p38 kinase, which are known to play important roles in apoptosis. Methods Cell death was evaluated using PC12 cells. Morphologic changes of cells, cellular membrane, and nuclei were observed. DNA fragmentation was electrophoretically assayed. Western blot analysis was performed to analyze phosphorylation of the MAPK family, cleavage of caspase-3 and poly(adenosine diphosphate-ribose) polymerase. Intracellular Ca2+ concentration was measured using a calcium indicator dye. Results Tetracaine-induced cell death was shown in a time- and concentration-dependent manner and characterized by nuclear condensation or fragmentation, membrane blebbing, and internucleosomal DNA fragmentation. Caspase-3 activation and phosphorylation of ERK, JNK, and p38 occurred in the cell death. PD98059, an inhibitor of ERK, enhanced tetracaine-induced cell death and JNK phosphorylation, whereas ERK phosphorylation was inhibited. Curcumin, an inhibitor of JNK pathway, attenuated the cell death. Increase of intracellular Ca2+ concentration was detected. In addition to the increase of ERK phosphorylation and the decrease of JNK phosphorylation, two Ca2+ chelators protected cells from death. Neither cell death nor phosphorylation of the MAPK family was caused by tetrodotoxin. Nifedipine did not affect tetracaine-induced apoptosis. Conclusions Tetracaine induces apoptosis of PC12 cells via the MAPK family. ERK activation protects cells from death, but JNK plays the opposite role. Toxic Ca2+ influx caused by tetracaine seems to be responsible for the cell death, but blocking of Na+ channels or L-type Ca2+ channels is unlikely involved in the tetracaine's action for apoptosis.

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