2025
Role of PLK4 inhibition in cancer therapy
Banik K, Hayman T. Role of PLK4 inhibition in cancer therapy. Cancer And Metastasis Reviews 2025, 44: 55. PMID: 40512236, DOI: 10.1007/s10555-025-10271-5.Peer-Reviewed Original ResearchConceptsAssociated with more advanced diseaseCancer therapyAssociated with tumor progressionMore advanced diseasePolo-like kinase 4PLK4 overexpressionMultiple cancer typesAdvanced diseaseTherapeutic resistanceClinical outcomesTumor progressionSmall molecule inhibitorsHuman tumorsCancer typesDNA-damaging agentsSerine-threonine kinaseCancerOncogenic processesTherapeutic gainTherapeutic targetPolo-like kinase 4 inhibitorPLK4 inhibitionKinase 4Genomic instabilityTherapy
2023
TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes
Boutagy N, Fowler J, Grabinska K, Cardone R, Sun Q, Vazquez K, Whalen M, Zhu X, Chakraborty R, Martin K, Simons M, Romanoski C, Kibbey R, Sessa W. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2218150120. PMID: 37695914, PMCID: PMC10515159, DOI: 10.1073/pnas.2218150120.Peer-Reviewed Original ResearchConceptsPyruvate dehydrogenase kinase 4Dehydrogenase kinase 4Lon proteasePyruvate dehydrogenase activityHistone acetylationMitochondrial metabolismKinase 4Specific gene lociPDH fluxEndothelial cellsSiRNA-mediated knockdownAcetyl-CoA generationLysine 27Gene transcriptionTCA fluxRNA sequencingHuman umbilical vein endothelial cellsProtein degradationHistone 3Gene locusUmbilical vein endothelial cellsNF-κB-dependent mechanismTricarboxylic acid cycle fluxVein endothelial cellsActive subunitAuthor Correction: Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)
Ha B, Yigit S, Natarajan N, Morse E, Calderwood D, Boggon T. Author Correction: Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Communications Biology 2023, 6: 794. PMID: 37524913, PMCID: PMC10390574, DOI: 10.1038/s42003-023-05176-4.Peer-Reviewed Original ResearchAbove the legal limit: Alcohol brings ER and mitochondria too close together
Guerra M, Nathanson M. Above the legal limit: Alcohol brings ER and mitochondria too close together. Cell Calcium 2023, 113: 102763. PMID: 37235972, PMCID: PMC10726477, DOI: 10.1016/j.ceca.2023.102763.Commentaries, Editorials and Letters
2022
Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)
Ha B, Yigit S, Natarajan N, Morse E, Calderwood D, Boggon T. Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Communications Biology 2022, 5: 1257. PMID: 36385162, PMCID: PMC9669019, DOI: 10.1038/s42003-022-04157-3.Peer-Reviewed Original ResearchConceptsP21-activated kinase 4Integrin adhesion receptorsMolecular basisAdhesion receptorsIntegrin β5Potential cellular rolesIntegrin β tailsKinase 4Membrane-proximal halfSubstrate-binding grooveSubstrate-binding siteSite-directed mutagenesisCellular rolesPhosphoacceptor sitesΒ tailExtracellular ligandsCytoplasmic signalingCytoplasmic tailKinase domainMultiple kinasesIntegrin complexΒ5 integrinsΒ5TailMutagenesis
2020
CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
Watt AC, Cejas P, DeCristo MJ, Metzger-Filho O, Lam EYN, Qiu X, BrinJones H, Kesten N, Coulson R, Font-Tello A, Lim K, Vadhi R, Daniels VW, Montero J, Taing L, Meyer CA, Gilan O, Bell CC, Korthauer KD, Giambartolomei C, Pasaniuc B, Seo JH, Freedman ML, Ma C, Ellis MJ, Krop I, Winer E, Letai A, Brown M, Dawson MA, Long HW, Zhao JJ, Goel S. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nature Cancer 2020, 2: 34-48. PMID: 33997789, PMCID: PMC8115221, DOI: 10.1038/s43018-020-00135-y.Peer-Reviewed Original ResearchConceptsSet of enhancersTranscription factor proteinsAP-1 transcriptional activityEndogenous retroviral elementsCell cycle arrestEnhancer landscapeCyclin-dependent kinase 4Cancer cell cycle arrestEnhancer activationCell chromatinApoptotic evasionTranscriptional activityPathway biologyRetroviral elementsApoptotic responsePharmacologic inhibitorsCancer cell immunogenicityFactor proteinNew enhancersKinase 4Cycle arrestLuminal differentiationCDK4/6 inhibitionCDK4/6 inhibitorsEnhancerRecognition of physiological phosphorylation sites by p21-activated kinase 4
Chetty AK, Sexton JA, Ha BH, Turk BE, Boggon TJ. Recognition of physiological phosphorylation sites by p21-activated kinase 4. Journal Of Structural Biology 2020, 211: 107553. PMID: 32585314, PMCID: PMC7395882, DOI: 10.1016/j.jsb.2020.107553.Peer-Reviewed Original ResearchConceptsLIM domain kinase 1Phosphorylation sitesΒ-cateninSerine/threonine protein kinaseActivation loop threonineThreonine protein kinasePhosphorylation of SerGroup II PAKsPhysiological phosphorylation siteKinase activity assaysP21-activated kinase 4Threonine substratesMode of recognitionSubstrate phosphorylationKinase groupSerine residuesProtein kinaseSerine substrateÅ resolutionCatalytic efficiencyKinase 1Substrate selectivityKinase 4Activity assaysPhosphorylationSerine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation
Su VL, Simon B, Draheim KM, Calderwood DA. Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation. Journal Of Biological Chemistry 2020, 295: 3269-3284. PMID: 32005669, PMCID: PMC7062153, DOI: 10.1074/jbc.ra119.009794.Peer-Reviewed Original ResearchConceptsIntegrin cytoplasmic domain-associated protein-1N-terminal regionNuclear accumulationP21-activated kinase 4Ser-10Nuclear roleSerine phosphorylationNuclear localizationPhosphorylation-mimicking substitutionsNuclear localization signalCell-cell junctionsSer-25Localization signalKRIT1 functionThreonine residuesAdaptor proteinKRIT1 lossSubcellular localizationNeurovascular dysplasiaBlood vessel integrityVascular developmentKinase 4Cultured cellsPhosphorylationProtein 1The extracellular sulfatase SULF2 promotes liver tumorigenesis by stimulating assembly of a promoter-looping GLI1-STAT3 transcriptional complex
Carr RM, Romecin Duran PA, Tolosa EJ, Ma C, Oseini AM, Moser CD, Banini BA, Huang J, Asumda F, Dhanasekaran R, Graham RP, Toruner MD, Safgren SL, Almada LL, Wang S, Patnaik MM, Roberts LR, Fernandez-Zapico ME. The extracellular sulfatase SULF2 promotes liver tumorigenesis by stimulating assembly of a promoter-looping GLI1-STAT3 transcriptional complex. Journal Of Biological Chemistry 2020, 295: 2698-2712. PMID: 31988246, PMCID: PMC7049957, DOI: 10.1074/jbc.ra119.011146.Peer-Reviewed Original ResearchConceptsGLI family zinc finger 1Transcriptional complexTarget genesSer/ThrSTAT3 target genesSULF2 overexpressionZinc finger 1Suppressor of cytokineTyrosine kinase 4Promoter conformationSpecific gene signaturesSTAT3 functionHuman orthologPromoter bindingTranscriptomic analysisConsensus sitesGli1 knockdownTransgenic mice overexpressingSignal transducerTranscription 3Molecular mechanismsFinger 1Kinase 4Hepatocellular carcinoma growthOverexpression
2019
Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells
Warth B, Palermo A, Rattray NJW, Lee NV, Zhu Z, Hoang LT, Cai Y, Mazurek A, Dann S, VanArsdale T, Fantin VR, Shields D, Siuzdak G, Johnson CH. Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells. Metabolites 2019, 9: 7. PMID: 30609717, PMCID: PMC6359333, DOI: 10.3390/metabo9010007.Peer-Reviewed Original ResearchProgression-free survivalBreast cancer cell metabolismEstrogen receptor antagonistCyclin-dependent kinase 4Breast cancer cellsCancer cell metabolismCombination chemotherapyMCF-7 cellsReceptor antagonistCombination chemotherapeuticsSurvival advantageSelective metabolic pathwaysMetabolic disruptionCancer cellsMetabolic pathwaysKinase 4Cancer metabolismSelective inhibitorPalbociclibSame metabolic pathwayDrugsMetabolismTranscriptomic changesCell modelCell metabolism
2017
Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia
Takao S, Chien W, Madan V, Lin D, Ding L, Sun Q, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang Y, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, Koeffler H. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 2017, 32: 616-625. PMID: 28904384, DOI: 10.1038/leu.2017.281.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAminopyridinesAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationCell SurvivalCytokinesDisease Models, AnimalFemaleHumansMaleMiceNADNicotinamide Phosphoribosyltransferasep21-Activated KinasesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaSignal TransductionXenograft Model Antitumor AssaysConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaP21-activated kinase 4Nicotinamide phosphoribosyltransferaseLymphoblastic leukemiaNAMPT inhibitionPatient-derived xenograft murine modelsPrognosis of patientsNicotinamide adenine dinucleotideNovel therapeutic strategiesNicotinic acid supplementationNovel dual inhibitorXenograft murine modelCell growth inhibitionAcid supplementationMurine modelTherapeutic strategiesRate-limiting enzymeCytogenetic abnormalitiesVivo efficacyPatientsNAMPT inhibitorsInhibitory effectDual inhibitorKinase 4CDK4/6 inhibition triggers anti-tumour immunity
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature 2017, 548: 471-475. PMID: 28813415, PMCID: PMC5570667, DOI: 10.1038/nature23465.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen PresentationBiological MimicryBreast NeoplasmsCell Cycle CheckpointsCell Line, TumorCell ProliferationCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Disease Models, AnimalFemaleHumansInterferonsMicePhosphorylationProtein Kinase InhibitorsRepressor ProteinsRNA, Double-StrandedSignal TransductionT-Lymphocytes, RegulatoryTranscriptomeViruses
2015
AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia
Zaha VG, Qi D, Su KN, Palmeri M, Lee HY, Hu X, Wu X, Shulman GI, Rabinovitch PS, Russell RR, Young LH. AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. Journal Of Molecular And Cellular Cardiology 2015, 91: 104-113. PMID: 26746142, PMCID: PMC4839186, DOI: 10.1016/j.yjmcc.2015.12.032.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCatalaseGene Expression RegulationHydrogen PeroxideMAP Kinase Kinase 4MiceMice, Inbred C57BLMice, TransgenicMitochondria, HeartMitochondrial Membrane Transport ProteinsMitochondrial Permeability Transition PoreMyocardial InfarctionMyocardial ReperfusionMyocardiumNecrosisProtein Kinase InhibitorsSignal TransductionTransgenesConceptsWild typeProtein kinase kinase 4Mitochondrial functionMitochondrial catalaseKinase-dead AMPKMitochondrial reactive oxygen productionStress-responsive kinaseMPTP openingC-Jun terminal kinaseInhibition of JNKPermeability transition pore openingMitochondrial permeability transition pore openingTransition pore openingAMPK inactivationResponsive kinaseTerminal kinaseCellular metabolismJNK activationMitochondrial integrityReactive oxygen productionTransgenic expressionCell survivalAMPKKinase 4Kinase
2014
Radiation-induced Changes in Levels of Selected Proteins in Peripheral Blood Serum of Breast Cancer Patients as a Potential Triage Biodosimeter for Large-scale Radiological Emergencies
Deperas-Kaminska M, Bajinskis A, Marczyk M, Polanska J, Wersäll P, Lidbrink E, Ainsbury EA, Guipaud O, Benderitter M, Haghdoost S, Wojcik A. Radiation-induced Changes in Levels of Selected Proteins in Peripheral Blood Serum of Breast Cancer Patients as a Potential Triage Biodosimeter for Large-scale Radiological Emergencies. Health Physics 2014, 107: 555-563. PMID: 25353241, DOI: 10.1097/hp.0000000000000158.Peer-Reviewed Original ResearchConceptsPeripheral blood serumBreast cancer patientsLarge-scale radiological emergencyCancer patientsApolipoprotein EConsistent dose-response relationshipBlood serumExternal beam radiotherapyIrradiation of skinKinase 4Dose-response relationshipLogistic regression modelsPartial-body exposuresPurpose of triageMultinomial logistic regression modelsBeam radiotherapyBlood samplesFetuin BMultivariate analysisBody exposureDifferent dosesRadiation-induced changesSerumProtein 7Factor X
2012
p21-Activated kinase 4 promotes prostate cancer progression through CREB
Park M, Lee H, Lee C, You S, Kim D, Park B, Kang M, Heo W, Shin E, Schwartz M, Kim E. p21-Activated kinase 4 promotes prostate cancer progression through CREB. Oncogene 2012, 32: 2475-2482. PMID: 22710715, DOI: 10.1038/onc.2012.255.Peer-Reviewed Original ResearchConceptsP21-activated kinase 4Prostate cancer progressionProstate cancerCancer progressionLNCaP-FGC cellsPromising therapeutic targetKinase 4Prostate cancer cellsDU145 prostate cancer cellsSpecific protein kinase A (PKA) inhibitorProtein kinase A (PKA) inhibitorElevation of cAMPNeuroendocrine differentiationNude miceTherapeutic targetActive PAK4Downstream effector pathwaysTumor progressionDecreased expressionTumor formationCancerCancer cellsPC-3ProgressionEffector pathways
2011
The Transcription Factor E74-Like Factor Controls Quiescence of Endothelial Cells and Their Resistance to Myeloablative Treatments in Bone Marrow
Sivina M, Yamada T, Park CS, Puppi M, Coskun S, Hirschi K, Lacorazza HD. The Transcription Factor E74-Like Factor Controls Quiescence of Endothelial Cells and Their Resistance to Myeloablative Treatments in Bone Marrow. Arteriosclerosis Thrombosis And Vascular Biology 2011, 31: 1185-1191. PMID: 21350194, PMCID: PMC3100289, DOI: 10.1161/atvbaha.111.224436.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Marrow CellsCell CycleCell ProliferationCellular SenescenceChlorocebus aethiopsCOS CellsCyclin-Dependent Kinase 4DNA-Binding ProteinsDrug ResistanceEndothelial CellsFluorouracilHumansMiceMice, Inbred C57BLMice, KnockoutMyeloablative AgonistsNeovascularization, PhysiologicNIH 3T3 CellsPromoter Regions, GeneticRNA InterferenceTime FactorsTranscription FactorsTransfectionConceptsBone marrowEndothelial cellsSinusoidal blood vesselsCyclin-dependent kinase 4 expressionBlood vesselsCyclin-dependent kinase 4Human umbilical vein endothelial cellsBone marrow endothelial cellsUmbilical vein endothelial cellsMurine endothelial cellsMarrow endothelial cellsVein endothelial cellsMyeloablative treatmentCD45- CD31Cell cycle entryProgenitor cellsMarrowKinase 4Hematopoietic systemCycle entryVascular networkCellsProliferationLineage-specific progenitor cellsVessels
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