Gotowe bibliografie tematyczne / MEK/ERK Signaling

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Gotowa bibliografia na temat „MEK/ERK Signaling”

Autor: Grafiati

Data publikacji: 6 września 2023

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Artykuły w czasopismach na temat "MEK/ERK Signaling"

Roy, Monideepa, Zhigang Li i David B. Sacks. "IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling". Molecular and Cellular Biology 25, nr 18 (15.09.2005): 7940–52. http://dx.doi.org/10.1128/mcb.25.18.7940-7952.2005.

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ABSTRACT IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.

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Eblen, Scott T., Jill K. Slack, Michael J. Weber i Andrew D. Catling. "Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes". Molecular and Cellular Biology 22, nr 17 (1.09.2002): 6023–33. http://dx.doi.org/10.1128/mcb.22.17.6023-6033.2002.

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ABSTRACT Utilizing mutants of extracellular signal-regulated kinase 2 (ERK2) that are defective for intrinsic mitogen-activated protein kinase or ERK kinase (MEK) binding, we have identified a convergent signaling pathway that facilitates regulated MEK-ERK association and ERK activation. ERK2-Δ19-25 mutants defective in MEK binding could be phosphorylated in response to mitogens; however, signaling from the Raf-MEK pathway alone was insufficient to stimulate their phosphorylation in COS-1 cells. Phosphorylation of ERK2-Δ19-25 but not of wild-type ERK2 in response to Ras V12 was greatly inhibited by dominant-negative Rac. Activated forms of Rac and Cdc42 could enhance the association of wild-type ERK2 with MEK1 but not with MEK2 in serum-starved adherent cells. This effect was p21-activated kinase (PAK) dependent and required the putative PAK phosphorylation sites T292 and S298 of MEK1. In detached cells placed in suspension, ERK2 was complexed with MEK2 but not with MEK1. However, upon replating of cells onto a fibronectin matrix, there was a substantial induction of MEK1-ERK2 association and ERK activation, both of which could be inhibited by dominant-negative PAK1. These data show that Rac facilitates the assembly of a mitogen-activated protein kinase signaling complex required for ERK activation and that this facilitative signaling pathway is active during adhesion to the extracellular matrix. These findings reveal a novel mechanism by which adhesion and growth factor signals are integrated during ERK activation.

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Yuan, Jimin, Wan Hwa Ng, Zizi Tian, Jiajun Yap, Manuela Baccarini, Zhongzhou Chen i Jiancheng Hu. "Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis". Science Signaling 11, nr 554 (30.10.2018): eaar6795. http://dx.doi.org/10.1126/scisignal.aar6795.

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RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A–associated mutants, are inhibited by traditional MEK inhibitors. However, we found that the increased homodimerization associated with the loop-deletion mutants promoted intradimer cross-phosphorylation of the activation loop and conferred differential resistance to MEK inhibitors both in vitro and in vivo. MEK1 dimerization was required both for its activation by the kinase RAF and for its catalytic activity toward the kinase ERK. Our findings not only identify a previously unknown group of MEK mutants and provide insight into some key steps in RAF-MEK-ERK activation but also have implications for the design of therapies targeting RAS-ERK signaling in cancers.

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Geest, Christian R., Miranda Buitenhuis, Marian J. A. Groot Koerkamp, Frank C. P. Holstege, Edo Vellenga i Paul J. Coffer. "Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors". Blood 114, nr 16 (15.10.2009): 3402–12. http://dx.doi.org/10.1182/blood-2008-08-175141.

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AbstractA plethora of extracellular stimuli regulate growth, survival, and differentiation responses through activation of the MEK-ERK MAPK signaling module. Using CD34+ hematopoietic progenitor cells, we describe a novel role for the MEK-ERK signaling module in the regulation of proliferation, survival, and cytokine production during neutrophil differentiation. Addition of the specific MEK1/2 inhibitor U0126 resulted in decreased proliferation of neutrophil progenitors. Conversely, transient activation of a conditionally active MEK1 mutant resulted in the expansion of progenitor cells, which thereafter differentiated normally into mature neutrophils. In contrast, chronic MEK1 activation was found to induce cell death of CD34+ neutrophil progenitors. Microarray analysis of CD34+ progenitor cells showed that activation of MEK1 resulted in changes in expression of a variety of cell-cycle modulating genes. Furthermore, conditional activation of MEK1 resulted in a dramatic increase in the expression of mRNA transcripts encoding a large number of hematopoietic cytokines, chemokines, and growth factors. These findings identify a novel role for MEK-ERK signaling in regulating the balance between proliferation and apoptosis during neutrophil differentiation, and they suggest the need for tight control of MEK-ERK activation to prevent the development of bone marrow failure.

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Du, Lili, i Jesse D. Roberts. "Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling". American Journal of Physiology-Lung Cellular and Molecular Physiology 316, nr 1 (1.01.2019): L20—L34. http://dx.doi.org/10.1152/ajplung.00319.2018.

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TGFβ activation during newborn lung injury decreases the expression of pulmonary artery smooth muscle cell (PASMC)-soluble guanylate cyclase (sGC), a critical mediator of nitric oxide signaling. Using a rat PASMC line (CS54 cells), we determined how TGFβ downregulates sGC expression. We found that TGFβ decreases sGC expression through stimulating its type I receptor; TGFβ type I receptor (TGFβR1) inhibitors prevented TGFβ-1-mediated decrease in sGCα1 subunit mRNA levels in the cells. However, TGFβR1-Smad mechanisms do not regulate sGC; effective knockdown of Smad2 and Smad3 expression and function did not protect sGCα1 mRNA levels during TGFβ-1 exposure. A targeted small-molecule kinase inhibitor screen suggested that MEK signaling regulates sGC expression in TGFβ-stimulated PASMC. TGFβ activates PASMC MEK/ERK signaling; CS54 cell treatment with TGFβ-1 increased MEK and ERK phosphorylation in a biphasic, time- and dose-dependent manner. Moreover, MEK/ERK activity appears to be required for TGFβ-mediated sGC expression inhibition in PASMC; MEK and ERK inhibitors protected sGCα1 mRNA expression in TGFβ-1-treated CS54 cells. Nuclear ERK activity is sufficient for sGC regulation; heterologous expression of a nucleus-retained, constitutively active ERK2-MEK1 fusion protein decreased CS54 cell sGCα1 mRNA levels. The in vivo relevance of this TGFβ-MEK/ERK-sGC downregulation pathway is suggested by the detection of ERK activation and sGCα1 protein expression downregulation in TGFβ-associated mouse pup hyperoxic lung injury, and the determination that ERK decreases sGCα1 protein expression in TGFβ-1-treated primary PASMC obtained from mouse pups. These studies identify MEK/ERK signaling as an important pathway by which TGFβ regulates sGC expression in PASMC.

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Hu, Wen-Yang, Parivash Afradiasbagharani, Ranli Lu, Lifeng Liu, Lynn A. Birch i Gail S. Prins. "Morphometric Analysis of Rat Prostate Development: Roles of MEK/ERK and Rho Signaling Pathways in Prostatic Morphogenesis". Biomolecules 11, nr 12 (4.12.2021): 1829. http://dx.doi.org/10.3390/biom11121829.

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The molecular mechanisms underlying prostate development can provide clues for prostate cancer research. It has been demonstrated that MEK/ERK signaling downstream of androgen-targeted FGF10 signaling directly induces prostatic branching during development, while Rho/Rho-kinase can regulate prostate cell proliferation. MEK/ERK and Rho/Rho kinase regulate myosin light chain kinase (MLCK), and MLCK regulates myosin light chain phosphorylation (MLC-P), which is critical for cell fate, including cell proliferation, differentiation, and apoptosis. However, the roles and crosstalk of the MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis have not been examined. In the present study, we used numerical and image analysis to characterize lobe-specific rat prostatic branching during postnatal organ culture and investigated the roles of FGF10-MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis. Prostates exhibited distinctive lobe-specific growth and branching patterns in the ventral (VP) and lateral (LP) lobes, while exogenous FGF10 treatment shifted LP branching towards a VP branching pattern. Treatment with inhibitors of MEK1/2, Rho, Rho kinase, or MLCK significantly inhibited VP growth and blocked branching morphogenesis, further supporting critical roles for MEK/ERK and Rho/Rho kinase signaling pathways in prostatic growth and branching during development. We propose that MLCK-regulated MLC-P may be a central downstream target of both signaling pathways in regulating prostate morphogenesis.

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Chen, Haixia, Renpeng Guo, Qian Zhang, Hongchao Guo, Meng Yang, Zhenfeng Wu, Shan Gao, Lin Liu i Lingyi Chen. "Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells". Proceedings of the National Academy of Sciences 112, nr 44 (19.10.2015): E5936—E5943. http://dx.doi.org/10.1073/pnas.1516319112.

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Inhibition of Mek/Erk signaling by pharmacological Mek inhibitors promotes self-renewal and pluripotency of mouse embryonic stem cells (ESCs). Intriguingly, Erk signaling is essential for human ESC self-renewal. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk-depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with misregulated expression of pluripotency genes, reduced cell proliferation, G1 cell-cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal. Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability, and self-renewal of mouse ESCs.

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Eblen, Scott T., Jill K. Slack-Davis, Adel Tarcsafalvi, J. Thomas Parsons, Michael J. Weber i Andrew D. Catling. "Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion". Molecular and Cellular Biology 24, nr 6 (15.03.2004): 2308–17. http://dx.doi.org/10.1128/mcb.24.6.2308-2317.2004.

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ABSTRACT Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.

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Zhan, Fenghuang, Lei Shi, Siqing Wang, Hongwei Xu, Thai M. Cao, Chunjiao Xu, Yong Wu, Maurizio Zangari, Guiyuan Li i Guido J. Tricot. "CKS1B Mediates SKP2/p27Kip1-Independent Myeloma Cell Survival and Disease Progression through Activation of MEK/ERK and JAK/STAT3 Signaling Pathways." Blood 114, nr 22 (20.11.2009): 126. http://dx.doi.org/10.1182/blood.v114.22.126.126.

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Abstract Abstract 126 We previously reported that CKS1B may influence myeloma (MM) cell growth and survival through SKP2/p27Kip1-dependent and -independent mechanisms. However, there is still no direct evidence to prove that CKS1B has a role in MM cell proliferation and disease progression. The present study was performed to establish its functional role and define CKS1B-mediated SKP2/p27Kip1-independent down-stream signaling pathways. CKS1B was over-expressed in OCI-MY5 and XG1 MM cell lines by lentivirus. Western blots confirmed CKS1B over-expression. Cells were cultured in medium containing 1% fetal bovine serum for 7 days. CKS1B-transfection resulted in increased cell proliferation compared to empty-vector (EV)-transfected controls. We also examined the role of CKS1B in myeloma resistance to the general used chemotherapeutic drugs, such as bortezomib (5nM), doxorubicin (100nM) and etoposide (100nM). Untreated cells and empty-vector (EV)-transfected cells with or without drug treatments served as controls. Significant less inhibition of cell growth and cell death was observed after drug treatment in CKS1B-transfected cells compared with controls (P < .05). To screen down-stream signaling pathways associated with cell growth and survival in OCI-MY5, MS28PE and XG-1 cells were transfected with specific CKS1B-shRNA, which resulted in decreased phosphorylation of MEK1/2, ERK1/2, STAT3, MCL1 and BCL2 compared to wild-type and control cells, transfected with scrambled CKS1B-shRNA. To confirm these results, we examined the alteration of STAT3, MEK/ERK and BCL2 signaling pathways in OCI-MY5 and XG1 cells after forced over-expression of CKS1B. Increased levels of p-MEK1/2, p-ERK1/2, p-STAT3, MCL1 and p-BCL2 were observed compared to the EV-transfected controls, confirming that CKS1B activates STAT3, MEK/ERK and BCL2 signaling pathways. In Contrast, SKP2 over-expression or p27Kip1 inhibition resulted in inhibition of STAT3 and MEK/ERK pathways with no remarkable changes inBCL2. Further investigation showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3, MEK/ERK and BCL2 signaling pathways only partially abrogated MM cell death and growth inhibition induced by CKS1B knockdown. Targeting either the STAT3, MEK/ERK or BCL2 signaling pathway with specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-over-expressing MM cells; their combination had a synergistic effect on cell death and growth inhibition. Our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in the therapy of aggressive CKS1B-overexpressing MM, which shows increased proliferation and drug-resistance Disclosures: No relevant conflicts of interest to declare.

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Popik, Waldemar, i Paula M. Pitha. "Inhibition of CD3/CD28-Mediated Activation of the MEK/ERK Signaling Pathway Represses Replication of X4 but Not R5 Human Immunodeficiency Virus Type 1 in Peripheral Blood CD4+T Lymphocytes". Journal of Virology 74, nr 6 (15.03.2000): 2558–66. http://dx.doi.org/10.1128/jvi.74.6.2558-2566.2000.

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ABSTRACT Binding of human immunodeficiency virus type 1 (HIV-1) to CD4 receptors induces multiple cellular signaling pathways, including the MEK/ERK cascade. While the interaction of X4 HIV-1 with CXCR4 does not seem to activate this pathway, viruses using CCR5 for entry efficiently activate MEK/ERK kinases (W. Popik, J. E. Hesselgesser, and P. M. Pitha, J. Virol. 72:6406–6413, 1998; W. Popik and P. M. Pitha, Virology 252:210–217, 1998). Since the importance of MEK/ERK in the initial steps of viral replication is poorly understood, we have examined the role of MEK/ERK signaling in the CD3- and CD28 (CD3/CD28)-mediated activation of HIV-1 replication in resting peripheral blood CD4+ T lymphocytes infected with X4 or R5 HIV-1. We have found that the MEK/ERK inhibitor U0126 selectively inhibited CD3/CD28-stimulated replication of X4 HIV-1, while it did not affect the replication of R5 HIV-1. Inhibition of the CD3/CD28-stimulated MEK/ERK pathway did not affect the formation of the early proviral transcripts in cells infected with either X4 or R5 HIV-1, indicating that virus reverse transcription is not affected in the absence of MEK/ERK signaling. In contrast, the levels of nuclear provirus in cells infected with X4 HIV-1, detected by the formation of circular proviral DNA, was significantly lower in cells stimulated in the presence of MEK/ERK inhibitor than in the absence of the inhibitor. However, in cells infected with R5 HIV-1, the inhibition of the MEK/ERK pathway did not affect nuclear localization of the proviral DNA. These data suggest that the nuclear import of X4, but not R5, HIV-1 is dependent on a CD3/CD28-stimulated MEK/ERK pathway.

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Rozprawy doktorskie na temat "MEK/ERK Signaling"

Lam, King-yin Andy. "Differential regulation of FOXM1 isoforms by RaF/MEK/ERK signaling". Click to view the E-thesis via HKUTO, 2010. http://sunzi.lib.hku.hk/hkuto/record/B44251014.

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Lam, King-yin Andy, i 林敬賢. "Differential regulation of FOXM1 isoforms by RaF/MEK/ERK signaling". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44251014.

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Solf, Andrea. "Transkriptionelle Netzwerke der RAS-abhängigen, MEK-ERK- vermittelten Transformation". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16295.

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Transkriptionelle Netzwerke (Transkriptionsfaktoren, epigenetische Modulatoren und spezifische Zielgene) stellen die unterste Ebene der zellinternen Signalübertragung dar. Eingebettet in verschiedene stimulusabhängige Signalwege bedienen sich ihre Komponenten genetischer und epigenetischer Mechanismen, um Zielgene transkrip-tionell zu regulieren und Veränderungen der Chromatinstruktur hervorzurufen. In der vorliegenden Arbeit wurde die hierarchische Organisation und Zusam-mensetzung des MEK-ERK-abhängig gesteuerten transkriptionellen Netzwerks und seine Veränderung im Zuge der HRAS-vermittelten onkogenen Transformation von HA1-Zellen untersucht. Viele Arbeiten haben sich bereits eingehend mit der Charak-terisierung einzelner Komponenten und Zielgene beschäftigt (Wagner et al. 2005, Reddy et al. 2002, Sun et al. 2006, Kapitel 1). Im Unterschied zu den zitierten Studien wurde in der vorliegenden Arbeit ein umfassendes Protokoll zur genomweiten De-chiffrierung transkriptioneller Netzwerke unter Kombination von experimentellen und bioinformatischen Methoden entwickelt und durchgeführt. Die Analyse ge-nomweiter Expressionsprofile un- und U0126-behandelter immortaler und HRASV12-transformierter humaner Nierenepithelzellen (HA1EB, HA1ER) erlaubte die Identifi-zierung von 138 auf- und 103 abregulierten genspezifischen IDs der RAS-ERK-abhängig gesteuerten Signalkaskade. Regulierte Transkriptionsfaktoren wurden i-dentifiziert und im Westernblot, sowie zum Teil mittels Durchflusszytometrie und RT-PCR validiert und nachfolgend transienten siRNA-Experimenten unterzogen. Für die Transkriptionsfaktoren ELK3, SRF und den hierarisch darunter liegenden Faktor FRA1 wurden Expressionsprofile der spezifischen siRNA-vermittelten Hemmung in beiden Zelllinien erstell und mit bioinformatischen Methoden (TRAP, GSEA-GO) a-nalysiert um direkte und indirekte sowie gemeinsame Zielgene zu ermitteln. Zusätz-lich wurde der Effekt auf phänotypischer Ebene (Softagar, MTT) überprüft. In der vorliegenden Arbeit ließ sich keine direkte Hierarchie der drei Transkrip-tionsfaktoren SRF, FRA1 und ELK3 bestätigen. Allerdings konnte zum ersten Mal eine gemeinsam regulierte Gruppe von Genen identifiziert werden, die darauf schließen lässt, dass die drei Transkriptionsfaktoren sowohl in HA1EB, als auch in HA1ER Teile eines gemeinsam regulierenden Netzwerks sind. Aus den Proliferationsexperimenten wurde zudem bestätigt, dass jeder Transkriptionsfaktor individuell eine essentielle Rolle bei der Promotion maligner Eigenschaften spielt. Für alle drei Transkriptionsfak-toren konnte eine RAS-abhängige starke Verschiebung der spezifisch angesteuerten Gene nachgewiesen werden. Diese Verschiebung wurde mittels TRAP und GSEA auch für alternative Regulatoren der spezifischen Zielgene festgestellt. Die nähere Analyse der FRA1-abhängigen Zielgene führte zu neuen Erkenntnis-sen zur Umordnung des Transkriptoms im Zuge der onkogenen Transformation. Die FRA1-spezifischen Zielgene in HA1EB und HA1ER weisen unterschiedliche Funktio-nalitäten auf. So wurden in HA1EB viele Gene identifiziert, die im Rahmen der Im-munantwort eine Rolle spielen und in HA1ER nicht reguliert werden. In den RAS-transformierten HA1ER konnten dagegen Gene identifiziert werden, die in der Tu-morprogression eine Rolle spielen (FRA1, STAT3, MTA1, TCFL5). Die Verifizierungen mittels qPCR und ChIP bestätigten 5 der 38 möglichen FRA1-Zielgene. Von diesen, FRA1, AEBP1, FRA1, TCFL5, NPAS2 und YWHAZ ist lediglich FRA1 bereits als FRA1-Zielgen beschrieben. Die Funktionen der neu identifizierten RAS-abhängigen FRA1-Zielgene untermauerten bereits bekannte Funktionen der FRA1-vermittelten Transkription (Differenzierung, Proliferation, zirkadiane Rhythmen, Apoptose) und erweitern sie um verschiedene Aspekte wie Metabolismus und Rückkopplungen in die Signaltransduktion, die noch nicht für die RAS-abhängige FRA1-vermittelte Transktiption beschrieben worden sind. Dazu gehören unter anderem Interaktionen mit TGFbeta, WNT, JAK/STAT und JNK. Daneben sind in den HA1ER eine Vielzahl von Regulatoren des RHO-Signalwegs identifiziert worden, was für FRA1 auf bisher unbekannte Interaktionen mit RAC/RHO-Signalwegen schließen lässt.
Transcriptional networks represent the final level of internal signal transmission. They are embedded in different signalling pathways and use genetic as well as epi-genetic mechanisms to regulate their according target genes. During oncogenic trans-formation they are undergoing massive rearrangements in composition, regulation and interaction. This leads to radical changes in the transcriptome and drives the on-cogenic phenotype of the according cells. My thesis employs the composition of the MEK-ERK-dependent transcriptional net-work and its alteration during the HRAS-oncogene-mediated transformation in HA1-cells. By commencing from already known components: SRF, Ternary Complex Fac-tors (TCF: SAP1, SAP2/ELK3, ELK1) and members of the AP1-complex (JUN, FOS-proteins) I analyzed the alteration in expression of secondary targets and their inter-action as well as their relation to the superior factors. Therefore I compared genome wide expression profiles (Affymetrix, HG-U133A) of immortal HA1EB and HRASV12-oncogene-transformed HA1ER-cells with and without U0126-induced MEK/ERK-inhibition and extracted several MEK/ERK-dependent transcription factors. Among them where FRA1 and ELK3, two transcription factors already known to be involved in oncogenesis and proliferation associated processes. ELK3 needs SRF as crucial binding partner to function. Therefor I also included SRF into the subsequent analysis. The three transcription factors function in different time-dependent hierarchy states so we supposed a putative hierachical network be-tween them. I established transient knockdown cells deriving from HA1EB and HA1ER for all three transcription factors and generated further expression profiles from them. Additionally I verified the importance of these transcription factors on survival and proliferation via MTT and Softagar experiments. Using different statis-tically and bioinformatical methods (GSEA, TRAP) in collaboration with the Max-Planck-Institute for molecular Genetics Berlin, several direct and indirect targets of these transcription factors were predicted. These were partially overlapping in all transcription factors. Also, in comparison of the immortal and the transformed cell line, a shift of functionalities and composition of the different target gene populations and collaborating factors could be detected for all three transcription factors. It was found that in HA1EB FRA1 seems more likely to regulate immunresponsive genes as well as genes associated with the cytoskeleton and nucleus organisation whereas in HA1ER FRA1 regulates a large group of transcription- and signalling-associated genes. Additionally it could be shown that in both cell lines FRA1 regulates genes in-volved in epigenetic processes as well as circadian rhythms which are known to be important aspects in oncogenic transformation. I verified 37 different putative target genes of FRA1 using qRT-PCR (Taqman) and partially also ChIP-analysis. Of these 37genes, 5 were fully validated as directly regu-lated targets of FRA1: FRA1, AEBP1, YWHAZ, NPAS2 and TCFL5. They imply functionalities connected to proliferation and differentiation (AEBP1, FRA1, TCFL5) as well as apoptosis (YWHAZ) cell cycle control and circadian rhythm (NPAS2, AEBP1), feedbacks into the signalling (YWHAZ, AEBP1) and metabolism (NPAS2, AEBP1). Summarised the work of this thesis contributes to the decipherment of the direct and indirect targets of the according transcription factors and strengthens the argument of a general and massive shift of the transcriptional network during oncogenic trans-formation of cells. The importance of all three transcription factors on the survival of genes could be proved via proliferation assays. Additionally the functionality of their according targets could be integrated into processes connected to oncogenic trans-formation.

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Fraser, Sasha. "Development of Dual-Pathway Inhibitors of Raf/MEK/ERK and PI3K/Akt Signaling Pathways". VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2619.

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In the present study, we designed a new chemical template that contains an oxindole moiety as potential dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. The design hypothesis is to evaluate whether the oxindole ring system will approximately orient functional groups in a similar manner to the thiazolidinedione moiety, and thus maintain biological activity as dual-pathway inhibitors of the Raf/MEK/ERK and PI3K/Akt signaling pathways. Furthermore, the oxindole ring will provide the flexibility to allow the introduction of various substituents on the oxindole moiety, thereby facilitating comprehensive SAR studies to further explore the biological activity.

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Hodge, Jacob G. "Regulation of the MEK/ERK signaling cascade by ADAM12 in triple-negative breast cancer cells". Thesis, Kansas State University, 2016. http://hdl.handle.net/2097/35228.

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Master of Science
Biochemistry and Molecular Biophysics Interdepartmental Program
Anna Zolkiewska
Mitogen-activated protein kinase (MAPK) signaling plays an important role in the proliferation, survival, and therapy resistance of breast cancer cells. Two important protein kinases involved in the MAPK pathway are MEK and ERK. The MEK/ERK signaling cascade can be stimulated by activation of the epidermal growth factor receptor (EGFR) upon binding of EGF-like ligands, which are released from cells by ADAM proteases. EGFR is frequently overexpressed in triple-negative breast cancer (TNBC), a particularly aggressive form of breast cancer. Our analysis of clinical data revealed that high expression of ADAM12, but not other ADAMs, in TNBC is associated with poor patient survival. Thus, we hypothesized that ADAM12 plays a critical role in the progression of TNBC, possibly by stimulating MEK/ERK activity in an EGFR-dependent manner. To test this hypothesis, ADAM12 was knocked-down (KD) in SUM159PT TNBC cells, which express high levels of the endogenous ADAM12 protein. An antibody array assay indicated a significant decrease in the activation of the MAPK pathway in SUM159PT cells after ADAM12 KD. The decrease in MAPK activity was further confirmed by Western blotting using phospho-MEK and phospho-ERK specific antibodies. Additionally, conditioned media from ADAM12-deficient SUM159PT cells failed to support the survival of MCF10A cells, suggesting that ADAM12 KD reduced the release of pro-survival growth factors from SUM159PT cells. Based upon this data, we propose that ADAM12 is a novel regulator of the MAPK pathway and a potential therapeutic target in breast cancer.

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Rapozo, Viviane Younes. "Sinalização da MAPK/ERK na diferenciaçãao da oligodendroglia: efeitos de inibidores da MEK sobre a morfologia e distribuição de proteínas de oligodendrócitos/mielina in vitro". Universidade do Estado do Rio de Janeiro, 2009. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=9529.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico
A via de sinalização da cinase regulada por fatores extracelulares, da família das proteínas cinases ativadas por mitógenos (MAPK/ERK) é importante tanto para a sobrevivência como para a progressão da diferenciação de oligodendrócitos. Neste trabalho, a via da MAPK/ERK foi avaliada na oligodendroglia in vitro com a utilização de inibidores da MEK. A morfologia celular, assim como a distribuição de proteínas foram analisadas em diferentes estágios de maturação da oligodendroglia. Culturas primárias de oligodendrócitos foram tratadas com os inibidores da MEK PD98059 ou U0126, aos 5 ou 11dias in vitro (div), por 30min, 24 ou 48h. A oligodendroglia foi distinguida com marcadores estágio-específicos: A2B5, 23nucleotídeo cíclico 3 fosfodiesterase (CNPase) e proteína básica de mielina (MBP), e classificada de acordo com sua morfologia em diferentes estágios de desenvolvimento. O tratamento aumentou significativamente o número de células com morfologia mais imatura e diminuiu o número de células maduras. Além disso, aumentou o número de células redondas e sem prolongamentos as quais não puderam ser classificadas em nenhum dos estágios de desenvolvimento da oligodendroglia. Os efeitos mais evidentes foram observados logo após o menor tempo de tratamento. Células redondas eram positivas para CNPase e MBP, porém não foram marcadas com A2B5 ou com NG2, indicando que seriam células maduras incapazes de estender ou manter seus prolongamentos. De fato, estas mudanças foram acompanhadas por alterações na distribuição de proteínas de oligodendrócitos como a MBP e a CNPase, assim como alterações em proteínas de citoesqueleto, como actina, tubulina e na cinase de adesão focal (FAK). A MBP foi observada nas células tratadas em um padrão de distribuição desorganizado e disperso, oposto ao padrão contínuo que é observado nas células das culturas controle. Além disso, o tratamento causou uma desorganização na distribuição da CNPase, actina e tubulina. Nas células das culturas controle, estas proteínas apresentam um padrão organizado compondo as estruturas de citoqueleto semelhantes a nervuras. Após um pequeno período de tratamento (30min), actina e tubulina apresentaram o mesmo padrão de marcação puntiforme que a CNPase apresentou. O tratamento também reduziu os pontos de adesão focal demonstrados pela FAK. Com o decorrer do tratamento, após 24 e 48h, actina e tubulina aparentavam estar se reorganizando em um padrão filamentar. Estes resultados indicam um efeito importante da via da MAPK/ERK na ramificação e alongamento dos prolongamentos dos oligodendrócitos, com possíveis consequências para a formação da bainha de mielina.
The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is important for both long-term survival and timing of the progression of oligodendrocyte differentiation. In this work, the MAPK/ERK signaling in oligodendroglia was studied in vitro by using MEK inhibitors. Cell morphology and distribution of proteins were analyzed in different stages of maturation. Primary cultures of oligodendroglia were treated with the MEK inhibitors PD98059 or U0126, at 5 or 11div for 30min, 24 or 48h. Oligodendroglial cells were distinguished by using stage specific markers: NG2 proteoglycan, A2B5, 23nucleotide-cyclic 3phosphodiesterase (CNPase) and myelin basic protein (MBP), and classified according to their morphology into different developmental stages. Treatment significantly increased the number of cells with more immature morphologies and decreased the number of mature cells. Furthermore, it increased the number of rounded cells that could not be classified into any of the oligodendroglial developmental stages. The strongest effects were usually observed shortly after treatment. Rounded cells were CNPase/MBP positive and they were not stained by anti-NG2 or A2B5, indicating that they were mature cells unable either to extend and/or to maintain their processes. In fact, these changes were accompanied by alterations in the distribution of the oligodendroglial proteins MBP and CNPase, and alterations in cytoskeleton proteins, as actin, tubulin and the focal adhesion kinase (FAK). MBP was observed in a continuous distribution in cell body and processes in control cultures. Furthermore, in treated cultures a disorganized pattern of distribution of CNPase, actin and tubulin was observed. In control cultures, these proteins compose the cytoskeleton vein-like structures. By the other side, after a short time of MEK inhibition (30min), actin and tubulin showed the same punctual pattern observed in CNPase distribution. Treatment also caused a reduction of focal adhesion sites showed by FAK. As treatment progressed, after 24 and 48h, actin and tubulin seemed to be rearranged into a filament-like pattern. These data showed an effect of the MAPK/ERK pathway on oligodendroglial branching, with possible consequences for the formation of the myelin sheath.

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Nörz, Dominik Sebastian [Verfasser], i Manfred [Akademischer Betreuer] Jücker. "Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-Inhibitors / Dominik Sebastian Nörz. Betreuer: Manfred Jücker". Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1093411325/34.

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Campbell, Sara J. "Mechanisms of Moraxella catarrhalis Induced Immune Signaling in the Pulmonary Epithelium". University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1268141520.

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Tham, Marius [Verfasser], i Petra [Akademischer Betreuer] Boukamp. "The role of stromal Wnt/Beta-catenin and epidermal Ras-Raf-MEK-ERK MAPK signaling in human squamous cell carcinoma / Marius Tham ; Betreuer: Petra Boukamp". Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180614097/34.

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Wieland, Anja. "Isoform-spezifische Funktionen mitogen-aktivierter Proteinkinasen in Transkriptionskontrolle und Proliferation". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16459.

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In vielen humanen Neoplasien findet sich eine erhöhte Aktivität des Raf-Mek-Erk-Signaltransduktionsweges. Zunächst wurde davon ausgegangen, dass diese erhöhte Aktivität hauptsächlich durch die Ras-Onkogene hervorgerufen wird. Doch mittlerweile konnten auch Mutationen der Raf Gene in humanen Neoplasien nachgewiesen werden. Gegen Raf und Mek konnten eine Anzahl von Enzyminhibitoren entwickelt werden. Der Nachteil vieler dieser Inhibitoren ist, dass sie nicht zwischen den einzelnen Kinaseisoformen unterscheiden können. In dieser Arbeit ist es nun das erste Mal gelungen, jede Komponente des Raf-Mek-Erk-Signaltransduktionsweges einzeln mittels RNA Interferenz effizient zu inhibieren. Dabei konnte die Rolle der verschiedenen Isoformen in der Proliferation, Morphologie und Genex-pression von transformierten Zellen definiert werden. In den NIH3T3-pEJ Zellen konnte A-Raf erstmals eine antiapoptotische Rolle zugewiesen werden. Diese Hemmung der Apoptose läuft möglicherweise über einen Mek2-abhängigen Weg und ist an die Mitochondrien gekoppelt. Für die beiden Mek Kinasen konnten unter-schiedliche Funktionen in der Signalweiterleitung gezeigt werden. Mek2 spielt die Hauptrolle in der Aktivierung der beiden Substratkinasen Erk1 und Erk2. Der Verlust der Mek1 Isoform wird dagegen möglicherweise durch eine erhöhte Expression von Mek2 kompensiert und wirkt sich nicht so stark auf die Phosphorylierung von Erk1/2 aus. Durch die Verwendung von Erk1 und Erk2 spezifischen siRNAs konnte eine Trennung zwischen der Proliferationsre-gulation und der Kontrolle der morphologischen Transformation herausgearbeitet werden. Durch die Verwendung von Mikroarrays ist es gelungen, beiden Phänotypen ein Genexpres-sionsprofil zuzuordnen. Neben Unterschieden zwischen den verschiedenen Kinaseisoformen konnten neue, potentielle Feedbacks beschrieben werden.
In many human neoplasia an increased activity of the RAF/MEK/ERK- signaling pathway is found. First it was assumed that this raised activity is caused primarily by the RAS onco-genes. However, meanwhile mutations in the RAF genes could be also proved in human neo-plasia. A number of enzyme inhibitors have been developed against the RAF and MEK pro-teins. The disadvantage of many of these inhibitors is that they cannot distinguish between the different kinase isoforms. In this work it has succeeded the first time to inhibit every compo-nent of the RAF/MEK/ERK- signaling pathway individually by means of interference RNA. Beside this, the role of the different isoforms in the proliferation, morphology and genetic profile of transformed cells could be defined. For the first time A-Raf could be assigned an anti-apoptotic role in NIH3T3-pEJ cells. This inhibition of the apoptosis possibly runs through a Mek2-dependent way and is coupled to the mitochondria. For both Mek kinases different functions could be shown in the downstream signaling. Mek2 plays the leading role in the activation of both downstream kinases Erk1 and Erk2. The loss of the Mek1 isoform expression is possibly compensated through an increased expression of Mek2 and does not affect the phosphorylation of Erk1 / 2 so strongly. A discri-mination between the regulation of proliferation and the control of the morphological trans-formation could be worked out by the use of Erk1 and Erk2 specific siRNAs. By the use of micorarray an expression profile of both phenotypes has assigned. Beside differences between the different kinases new, potential feedback pathways could be described.

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Książki na temat "MEK/ERK Signaling"

Alves, Ines Teles, Jan Trapman i Guido Jenster. Molecular biology of prostate cancer. Redaktor James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0059.

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Prostate cancer is a heterogeneous disease that arises through the acquisition of key malignant hallmarks. At the molecular level, prostate tumours are dependent upon the androgen receptor pathway, which affects cell function, growth, and behaviour through downstream androgen-regulated genes. Prostate cancer requires this activity and manipulates the AR pathway to maintain signalling. For example, mutation of the AR (to bind ligands other than androgens) or amplification/duplication of the AR allows signalling to continue in the absence of testosterone. Around 50% of prostate cancers have a gene fusion between the androgen-regulated component of the TMPRSS2 gene and a transcription factor (e.g. ETS family members ERG and ETV1). This results in aberrant androgen stimulated cell growth. Current research is using molecular knowledge to identify biomarkers, such as PCA3, and new therapies, such as enzalutamide or abiraterone acetate.

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Części książek na temat "MEK/ERK Signaling"

McCubrey, James A., Linda S. Steelman, Jörg Bäsecke i Alberto M. Martelli. "Raf/MEK/ERK Signaling". W Targeted Therapy of Acute Myeloid Leukemia, 275–305. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1393-0_14.

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Galabova-Kovacs, Gergana, i Manuela Baccarini. "Deciphering Signaling Pathways In Vivo: The Ras/Raf/Mek/Erk Cascade". W MAP Kinase Signaling Protocols, 421–31. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-795-2_26.

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McCubrey, James A., Linda S. Steelman, William H. Chappell, Stephen L. Abrams, Richard A. Franklin, Giuseppe Montalto, Melchiorre Cervello i in. "New Agents and Approaches for Targeting the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR Cell Survival Pathways". W Cell Death Signaling in Cancer Biology and Treatment, 331–72. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-5847-0_13.

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Le, Nhat-Tu, Nguyet Minh Hoang, Keigi Fujiwara i Jun-ichi Abe. "MEK5/ERK5". W Encyclopedia of Signaling Molecules, 3052–74. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_617.

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Le, Nhat-Tu, Nguyet Minh Hoang, Keigi Fujiwara i Jun-ichi Abe. "MEK5/ERK5". W Encyclopedia of Signaling Molecules, 1–23. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_617-1.

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Gewies, Andreas, Jürgen Ruland, Alexey Kotlyarov, Matthias Gaestel, Shiri Procaccia, Rony Seger, Shin Yasuda i in. "MEK5/ERK5". W Encyclopedia of Signaling Molecules, 1065–74. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_617.

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Gewies, Andreas, Jürgen Ruland, Alexey Kotlyarov, Matthias Gaestel, Shiri Procaccia, Rony Seger, Shin Yasuda i in. "Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK) Kinases 1/2 (MEK1/2)". W Encyclopedia of Signaling Molecules, 1081. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100810.

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Gewies, Andreas, Jürgen Ruland, Alexey Kotlyarov, Matthias Gaestel, Shiri Procaccia, Rony Seger, Shin Yasuda i in. "MEK5/ERK5: Mitogen-Activated Protein Kinase 5/Extracellular Signal-Regulated Kinase 5". W Encyclopedia of Signaling Molecules, 1074. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100786.

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See, Wendy L., i Joydeep Mukherjee. "Targeting the RAS-RAF-MEK-ERK Signaling Pathway in Gliomas". W Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy, 323–32. Elsevier, 2018. http://dx.doi.org/10.1016/b978-0-12-812100-9.00022-x.

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McMahon, Martin. "Steroid receptor fusion proteins for conditional activation of raf-MEK-ERK signaling pathway". W Methods in Enzymology, 401–17. Elsevier, 2001. http://dx.doi.org/10.1016/s0076-6879(01)32218-8.

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Streszczenia konferencji na temat "MEK/ERK Signaling"

Kaur, Navneet, Robert Lewis, Adrian Black i Jennifer Black. "Abstract 3466: Growth inhibitory MEK-ERK signaling in the intestinal epithelium". W Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3466.

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Rupp, Carina, Thomas Rösner, Ulrike Bauer, Birgit Kohnke-Ertel, Christian Lechler, Saumya Manmadhan, Katja Steiger i in. "Relevance of MEK/ERK signaling in biliary differentiation in murine liver cancer". W 38. Jahrestagung der Deutsche Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag, 2022. http://dx.doi.org/10.1055/s-0041-1740779.

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Rupp, C., T. Rösner, U. Bauer, B. Kohnke-Ertel, C. Lechler, K. Steiger, C. Mogler i in. "MEK/ERK signaling downstream of mutant Kras drives biliary differentiation in murine cholangiocarcinoma". W Viszeralmedizin 2021 Gemeinsame Jahrestagung Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Sektion Endoskopie der DGVS, Deutsche Gesellschaft für Allgemein und Viszeralchirurgie (DGAV). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1733626.

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Shah, Arpit D., Michael Bouchard i Adrian C. Shieh. "Abstract 4155: Interstitial fluid flow-induced hepatocellular carcinoma cell invasion requires MEK/ERK signaling". W Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-4155.

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Xing, Yiming, Changgong Li, Zea Borok i Parviz Minoo. "Lack Of Morphogenetic Orchestration Associated With Reduced ERK/MEK Signaling In Pten Lung Endoderm". W American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a3547.

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Stowe, Irma B., Timothy Stowe, Frank McCormick i Ellen Mercado. "Abstract LB-151: Spred1 and neurofibromin interact to negatively regulate Ras/Raf/MEK/ERK signaling". W Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-lb-151.

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Oh, You-Take, Weilong Yao, Jiusheng Deng, Ping Yue i Shi-Yong Sun. "Abstract LB-101: The expression of death receptor 4 is positively regulated by MEK/ERK signaling and suppressed upon MEK inhibition". W Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-lb-101.

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Warr, Matthew R., Angie Hammond, Grace Park, Nathan Wright i James Taylor. "THU0055 TPL2 INHIBITION SUPPRESSES MEK-ERK INFLAMMATORY SIGNALING AND PROINFLAMMATORY CYTOKINE PRODUCTION IN PRIMARY HUMAN MONOCYTES". W Annual European Congress of Rheumatology, EULAR 2019, Madrid, 12–15 June 2019. BMJ Publishing Group Ltd and European League Against Rheumatism, 2019. http://dx.doi.org/10.1136/annrheumdis-2019-eular.2512.

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Ebi, Hiromichi, Carlotta Costa, Anthony Faber, Dejan Juric, Patricia Della Pelle, Youngchul Song, Seiji Yano, Mari Mino-Kenudson, Cyril H. Benes i Jeffrey A. Engelman. "Abstract A29: PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1." W Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a29.

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Raporty organizacyjne na temat "MEK/ERK Signaling"

Dickman, Martin B., i Oded Yarden. Involvement of the PKA and MAPK signal transduction pathways in sclerotial morphogenesis in Sclerotinia sclerotiorum. United States Department of Agriculture, wrzesień 2007. http://dx.doi.org/10.32747/2007.7695861.bard.

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The long-term goals of our research are to understand the regulation of sclerotial development and pathogenicity in S. sclerotiorum. The focus in this project is on the elucidation of the signaling events and environmental cues involved in the regulation of these processes, utilizing and continuously developing tools our research groups have established and/or adapted for analysis of S. sclerotiorum. Our stated specific objectives were to: 1. Follow activities and function of S. sclerotiorumPKA. 2. Identify and functionally evaluate effectors of the S. sclerotiorumERK-likeMAPK signaling pathway. 3. Perform structural and functional analysis of genes whose expression is altered under conditions affecting either PKA and/or MAPK. As can be seen below, we have not only met most of the listed goals, but have also expanded our research. We have been working both together and in parallel in order to advance our goals. We have jointly shown how an ERK-likeMAPK is required sclerotia formation. We have analyzed, in parallel, the involvement of PKA in sclerotiogenesis and, interestingly, have reached some overlapping results but each group has provided a slightly different interpretation to the picture obtained. It will be interesting to see how this aspect of the analysis progresses, as we jointly tackle the yet unresloved issues. We have also made progress on the analysis of ser/thr phosphatases (specifically – calcineurin, which has been reported to interact with PKA) and PP2A in S. sclerotiorum as well as the S. sclerotiorum rasgene, which we have cloned and shown induces SMK1, the ERK-like kinase responsible for sclerotia formation. In addition to the time and efforts invested towards reaching the specific goals mentioned, both PIs are actively involved in a major international effort to sequence and annotate the entire S. sclerotiorum genome. Though time consuming (and perhaps requiring divergence of some time and resources from the original workplan), we have given this topic a very high priority to this effort as the long term implications of the success of this venture are enormous.

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Elmann, Anat, Orly Lazarov, Joel Kashman i Rivka Ofir. therapeutic potential of a desert plant and its active compounds for Alzheimer's Disease. United States Department of Agriculture, marzec 2015. http://dx.doi.org/10.32747/2015.7597913.bard.

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We chose to focus our investigations on the effect of the active forms, TTF and AcA, rather than the whole (crude) extract. 1. To establish cultivation program designed to develop lead cultivar/s (which will be selected from the different Af accessions) with the highest yield of the active compounds TTF and/or achillolide A (AcA). These cultivar/s will be the source for the purification of large amounts of the active compounds when needed in the future for functional foods/drug development. This task was completed. 2. To determine the effect of the Af extract, TTF and AcA on neuronal vulnerability to oxidative stress in cultured neurons expressing FAD-linked mutants.Compounds were tested in N2a neuroblastoma cell line. In addition, we have tested the effects of TTF and AcA on signaling events promoted by H₂O₂ in astrocytes and by β-amyloid in neuronal N2a cells. 3. To determine the effect of the Af extract, TTF and AcA on neuropathology (amyloidosis and tau phosphorylation) in cultured neurons expressing FAD-linked mutants. 4. To determine the effect of A¦ extract, AcA and TTF on FAD-linked neuropathology (amyloidosis, tau phosphorylation and inflammation) in transgenic mice. 5. To examine whether A¦ extract, TTF and AcA can reverse behavioral deficits in APPswe/PS1DE9 mice, and affect learning and memory and cognitive performance in these FAD-linked transgenic mice. Background to the topic.Neuroinflammation, oxidative stress, glutamate toxicity and amyloid beta (Ab) toxicity are involved in the pathogenesis of Alzheimer's diseases. We have previously purified from Achilleafragrantissimatwo active compounds: a protective flavonoid named 3,5,4’-trihydroxy-6,7,3’-trimethoxyflavone (TTF, Fl-72/2) and an anti-inflammatory sesquiterpenelactone named achillolide A (AcA). Major conclusions, solutions, achievements. In this study we could show that TTF and AcA protected cultured astrocytes from H₂O₂ –induced cell death via interference with cell signaling events. TTF inhibited SAPK/JNK, ERK1/2, MEK1 and CREBphosphorylation, while AcA inhibited only ERK1/2 and MEK1 phosphorylation. In addition to its protective activities, TTF had also anti-inflammatory activities, and inhibited the LPS-elicited secretion of the proinflammatorycytokinesInterleukin 6 (IL-6) and IL-1b from cultured microglial cells. Moreover, TTF and AcA protected neuronal cells from glutamate and Abcytotoxicity by reducing the glutamate and amyloid beta induced levels of intracellular reactive oxygen species (ROS) and via interference with cell signaling events induced by Ab. These compounds also reduced amyloid precursor protein net processing in vitro and in vivo in a mouse model for Alzheimer’s disease and improvedperformance in the novel object recognition learning and memory task. Conclusion: TTF and AcA are potential candidates to be developed as drugs or food additives to prevent, postpone or ameliorate Alzheimer’s disease. Implications, both scientific and agricultural.The synthesis ofAcA and TTF is very complicated. Thus, the plant itself will be the source for the isolation of these compounds or their precursors for synthesis. Therefore, Achilleafragrantissima could be developed into a new crop with industrial potential for the Arava-Negev area in Israel, and will generate more working places in this region.

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Seiler, Andreas, Aina Winsvold, Mattias Olsson, Svein Morten Eilertsen i Carolin Berndt. VILTVARNING: Test av nya tekniska åtgärder för att minska antalet viltpåkörningar på järnväg. Swedish University of Agricultural Sciences, 2022. http://dx.doi.org/10.54612/a.7pbjcv25mc.

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Viltolyckorna på järnväg har ökat stadigt de senaste åren – inte bara i Sverige och Norge utan även internationellt. För att minska de ekologiska och socioekonomiska effekterna behövs bättre åtgärder och nya åtgärdsstrategier. Stängsel och faunapassager har vanligtvis god effekt men är dyra lösningar som kan motiveras endast längs särskilt olycksdrabbade sträckor. De behöver därför kompletteras med åtgärder som ger skydd längs huvuddelen av järnvägsnätet. Viltvarslingsprosjektets centrala mål er att bidra till att skapa säkrare väg- och järnvägstransporter i Norden med en infrastruktur som är väl integrerat i landskapet så att naturliga processer och viktiga ekologiska tjänster kan bibehållas. Projektet är en gränsöverskridande satsning inom insatsområde Innovativa Miljöer der svenske og norske forskningsmiljøer sammen med berörda myndigheter, tågbolag, teknologiutviklere, samt andra relevanta aktörer utvikler og tester nya tekniska lösningar. Forskningen har lagt et godt grunnlag for å kunne videreutvikle de tekniske løsningene og gjøre dem mest mulig relevante for formålet å drive vilt bort fra jernbanesporene når toget skal passere. Flest mulige skal ha tilgang til kunnskapen som genereres i prosjektet og dette muliggjør kommersiell utvikling av slike tekniske systemer. Videre har vi bidratt til internasjonal kunnskapsproduksjon og kunnskapsutveksling innenfor problematikken rundt dyrepåkjørsler. Dyrepåkjørsler både på veg og jernbane som involverer større pattedyr har økt betydelig i både Norge, Sverige og resten av Europa i løpet av de siste 40 år. Slike ulykker fører ofte til kostbare skader på kjøretøyet og at det påkjørte dyret påføres store skader eller dør. Ifølge det norske hjorteregisteret har nesten 64.000 større dyr blitt påkjørt på norske veier og jernbaner de siste fem årene. I underkant av 10 prosent av alle viltpåkjørsler skjer med tog. Mellan 4.000–6.000 påkörningar med vilda djur och ren har registrerats längs järnvägsnätet i Sverige per år under det senaste decenniet och trenden är ökande. Mörkertalet i statistiken är okänt men förväntas vara stort i både Norge och Sverige. Metoderna bygger på att med utvalda akustiska signaler skapa en kontrollerad flyktrespons hos djuren när tåg skall passera, och därmed avvärja djuren från infrastrukturen när olycksrisken är som störst. Metoden ska kunna tillämpas där fysiska åtgärder som t ex viltstängsel eller viltpassager inte är möjliga eller där de traditionella åtgärderna behöver kompletteras. Åtgärdskonceptet inkluderar både en stationär lösning vid järnväg med mycket trafik och hög hastighet, och som en mobil lösning för tågfordon längs med järnvägen med mindre trafik och lägre hastighet. Resultaten kommer även att kunna tillämpas i andra sammanhang, t ex för att säkra öppningar i viltstängsel längs väg och vid tunnelmynningar. Projektet utgör en plattform för gränsöverskridande forskning om viltvarning, och en grundförutsättning för att företag och myndigheter skall kunna tillämpa och utveckla metoder för att minska problematiken med viltpåkörning. Prosjektet inkluderer tre arbeidspakker: - AP1) Kontrollerade experiment med det stasjonære skremmesystemet «Motion Activated Scare System» (MASS) der vi undersøker dyrenes respons på olika skrämselsignaler på platser längs järnväg. I projektet har vi kunnat vidareutveckla både funktion och utformning av de tekniska enheterna som vi använder för att avvärja vilt från spåren. De stationära MASS-enheterna har använts vid totalt 29 platser längs järnväg. När MASS-enheterna spelade upp ljudet av en människoröst lämnade klövdjuren området där vi filmade i ca 88 % av fallen. Olika ljud från tåg och järnväg (Bell, Horn, Train) inducerar en något lägre flyktrespons, men trots allt avvärjs djuren i medeltal ca 65 % av tillfällena med dessa ljudtyper. Den vanligaste rörelseriktningen (ca 57 %) var att djuren rörde sig bort från järnvägen efter att de skrämts, medan en lägre andel (ca 22 %) rörde sig mot och över järnvägen. - AP2) Framtagning och test av mobil skrämselenhet «Driver Activated Scare System» (DASS) som er installert innenfor frontruten på ulike togsett og aktiveres av togførere når vedkommende ser dyr på/ved jernbanelinja. I pilotstudien använde vi DASS-enheter för att utforska hur klövvilt, särskilt rådjur (Capreolus capreolus) och älg (Alces alces) reagerar på mötande tåg. Interaktionerna analyserades både ur djurens perspektiv (deras beteende, hur de flydde från tåget etc.) och lokförarnas möjligheter att se djuren från tåghytten (detektionsavstånd). Siden mars 2022 har slike enheter vært i bruk langs Nordlands- og Rørosbanen i Norge. I juni ble DASS-enheter tatt i bruk langs Gjøvikbanen. I tillegg har togførere filmet Kinnekullebanan i Sverige siden slutten av april 2022. Totalt ble det filmet vilt i 192 tillfeller med DASS-enhetene. Totalt ble det registrert 460 individer. Dovhjort (N=230) var den absolutt vanligste arten i forsøkene, etterfulgt av rådyr (N=100). Elg ble registrert på 5 filmer, og kronhjort i 8 filmer. I filmene fra togførerne kunne vi oppdage dyr som sto oppe på selve banelegemet i gjennomsnitt 157 meter fra toget vilket är mycket nära för att ge tillräckligt tid åt både lokförare och djuret att reagera. På grund av försenade tillstånd i arbete med högtalare samt ej tillräckliga tekniska lösningar kunde vi inte montera en högtalare utanpå tåget för att spela upp varningsljud för tester. Istället fokuserade vi på att studera effekten av befintliga alternativ för signalering. Studien kommer att fortsätta under nästa år och arbetet med att hitta en lämplig högtalarlösning pågår. - AP3) Kommunikasjon og prosjektledelse. En bra kommunikation och samverkan med berörda myndigheter, företag och intresseorganisationer är en grundförutsättning när praktiska åtgärder ska utvecklas och implementeras. Viltvarslingsprosjektet inkluderer mange aktører og samarbeidspartnere, både faglige og praktiske, nasjonalt og internasjonalt. Blant allmennheten og blant togaktørene har det i lang tid vært opprørthet og fortvilelse over det store antallet dyr som hvert år dør i kollisjoner med tog og på vei. Det har derfor skapt stor medial interesse når vi nå har begynt å få forskningsresultater som kan bidra til å minske påkjørslene, det vil si både redusering av dyrelidelsene og skadene på togene. I løpet av prosjekttiden med Interreg har det vært en meget hektisk periode med mye media-dekning og kommunikasjon utad om viltprosjektet. Det har vært et 30-talls nyhetsoppslag om prosjektet i nasjonale og lokale norske og svenske aviser. Samtidigt har projektet varit i kontakt med företag och myndigheter i frågor gällande tillämpningen av systemen och hjälp vid experimenten. Det på går flera parallella studer kring järnvägssäkerhet som har beröring till viltvarningsprojektet och där synergier kan tas till vara.Även internationellt bedrivs jämförbar forskning som vi har etablert ett utbyte med och söker nya samarbetsformer. Våra studier visar hittills att det är mycket sannolikt att ett varningssystem som bygger på akustiska signaler, främst den mänskliga rösten, kan vara kostnadseffektiva åtgäder mot djurpåkörnignar på järnväg. En kommersiell, järnvägsbaserad lösning anses vara mycket möjlig. För att nå fram till en tågbaserad lösning däremot behövs fortsatta studier och vidare teknisk utveckling. Vi söker därför för nya medel under 2023-2024 för att kunna driva utvecklingen fram mot implementering och konkreta demonstrationsprojekt.

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