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dc.contributor.authorKanellis, John-
dc.contributor.authorKandane, Rangi K-
dc.contributor.authorEtemadmoghadam, Dariush-
dc.contributor.authorFraser, Scott A-
dc.contributor.authorMount, Peter F-
dc.contributor.authorLevidiotis, Vicki-
dc.contributor.authorKemp, Bruce E-
dc.contributor.authorPower, David Anthony-
dc.identifier.citationImmunology and Cell Biologyen_US
dc.description.abstractAMP-activated protein kinase (AMPK) is a key energy sensor, known to regulate energy metabolism in diverse cell types. Hypoxia is encountered frequently in the microenvironments of inflammatory lesions and is a critical regulator of function in inflammatory cells. Energy deficiency is one of the consequences of hypoxia, but its potential role in modulating leucocyte function has received little attention. Using micropore chemotaxis assays to assess migratory responses of the monocyte-like cell line U937, it was found that the AMPK activators AICAR and phenformin rapidly reduced random migration (chemokinesis) as well as chemotaxis due to stromal cell-derived factor (SDF)1alpha. There was an approximate 50% reduction in both chemokinesis and chemotaxis following 30 min preincubation with both AICAR and phenformin (P < 0.01), and this continued with up to 24 h preincubation. The binding of SDF1alpha to its receptor CXCR4 was unaltered, suggesting AMPK was acting on downstream intracellular signalling pathways important in cell migration. As AMPK and statins are known to inhibit HMG CoA reductase, and both reduce cell migration, the effect of mevastatin on U937 cells was compared with AMPK activators. Mevastatin inhibited cell migration but required 24 h preincubation. As expected, the inhibitory effect of mevastatin was associated with altered subcellular localization of the Rho GTPases, RhoA and cdc42, indicating decreased prenylation of these molecules. Although the effect of AMPK activation was partially reversed by mevalonate, this was not associated with altered subcellular localization of Rho GTPases. The data suggest that activation of AMPK has a general effect on cell movement in U937 cells, and this is not due to inhibition of HMG CoA reductase. These are the first data to show an effect of AMPK on cell movement, and suggest a fundamental role for energy deficiency in regulating cellular behaviour.en_US
dc.subject.otherAminoimidazole Carboxamide.analogs & derivatives.pharmacologyen
dc.subject.otherCell Movement.drug effectsen
dc.subject.otherChemokine CCL2.pharmacologyen
dc.subject.otherChemokine CXCL12en
dc.subject.otherChemokines, CXC.pharmacologyen
dc.subject.otherChemotaxis.drug effectsen
dc.subject.otherDose-Response Relationship, Drugen
dc.subject.otherDrug Synergismen
dc.subject.otherEnzyme Activationen
dc.subject.otherEnzyme Activators.pharmacologyen
dc.subject.otherLovastatin.analogs & derivatives.pharmacologyen
dc.subject.otherMevalonic Acid.analogs & derivatives.pharmacologyen
dc.subject.otherProtein Kinases.metabolism.physiologyen
dc.subject.otherU937 Cellsen
dc.subject.otherrho GTP-Binding Proteins.metabolismen
dc.titleActivators of the energy sensing kinase AMPK inhibit random cell movement and chemotaxis in U937 cells.en_US
dc.typeJournal Articleen_US
dc.identifier.journaltitleImmunology and Cell Biologyen_US
dc.type.austinJournal Articleen
item.fulltextNo Fulltext-
item.openairetypeJournal Article-
item.languageiso639-1en- for Breathing and Sleep- (University of Melbourne)-
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