Featured Publications
Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation
Schneekloth JS, Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, Crews CM. Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. Journal Of The American Chemical Society 2004, 126: 3748-3754. PMID: 15038727, DOI: 10.1021/ja039025z.Peer-Reviewed Original ResearchConceptsGreen fluorescent proteinProtein functionCell biological questionsGenetic model systemUbiquitin-proteasome pathwayChemical knockoutTargeted degradationBiological questionsProtein degradationGenetic strategiesGenetic controlGenetic lossTarget proteinsFluorescent proteinChimeric moleculesCultured cellsFKBP12 ligandsProteinProtein levelsModel systemWestern blotGeneral strategyFunction analysisVivo examplesFluorometric analysis
2001
Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation
Sakamoto K, Kim K, Kumagai A, Mercurio F, Crews C, Deshaies R. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 8554-8559. PMID: 11438690, PMCID: PMC37474, DOI: 10.1073/pnas.141230798.Peer-Reviewed Original ResearchConceptsSkp1-CullinF-box complexAttachment of ubiquitinUbiquitin-dependent proteolysisMetAP-2Disease-causing proteinsMethionine aminopeptidase 2SCF complexBeta-TRCPConditional inactivationBox complexChimeric moleculesProteinUbiquitinationIntracellular levelsUbiquitinChimeric compoundsAngiogenesis inhibitorsHRT1ComplexesPhosphopeptidesDomainProteolysisEnzymeDegradationThe ubiquitin‐proteasome pathway and proteasome inhibitors
Myung J, Kim K, Crews C. The ubiquitin‐proteasome pathway and proteasome inhibitors. Medicinal Research Reviews 2001, 21: 245-273. PMID: 11410931, PMCID: PMC2556558, DOI: 10.1002/med.1009.Peer-Reviewed Original ResearchConceptsUbiquitin-proteasome pathwayComplex biochemical machineryHuman diseasesDiverse cellular processesImportant cellular substratesMajor cellular networksCellular processesBiochemical machineryProtein degradationNatural proteasome inhibitorsCellular substratesCentral playerIntracellular processesMode of actionProteasome inhibitorsPathwayMolecular probesInhibitorsPotential therapeutic agentProteasomeImportant componentMachineryRegulationTherapeutic agentsCells adapted to the proteasome inhibitor 4-hydroxy- 5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone require enzymatically active proteasomes for continued survival
Princiotta M, Schubert U, Chen W, Bennink J, Myung J, Crews C, Yewdell J. Cells adapted to the proteasome inhibitor 4-hydroxy- 5-iodo-3-nitrophenylacetyl-Leu-Leu-leucinal-vinyl sulfone require enzymatically active proteasomes for continued survival. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 513-518. PMID: 11149939, PMCID: PMC14618, DOI: 10.1073/pnas.98.2.513.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid Chloromethyl KetonesAminopeptidasesAnimalsAntigen PresentationAntigensBoronic AcidsBortezomibCD8-Positive T-LymphocytesCell SurvivalCysteine EndopeptidasesDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDrug ResistanceEndopeptidasesEnzyme ActivationH-2 AntigensLeupeptinsLymphoma, T-CellMiceMultienzyme ComplexesNeoplasm ProteinsOligopeptidesPeptide FragmentsPhenolsProtease InhibitorsProteasome Endopeptidase ComplexProtein Processing, Post-TranslationalPyrazinesSelection, GeneticSerine EndopeptidasesSulfonesThymus NeoplasmsTumor Cells, CulturedTumor Suppressor Protein p53TyramineUbiquitinsConceptsII activityLarge proteolytic complexSpecific proteasome inhibitorInhibitor 4Degradation of p53Ala-AlaProteolytic complexPolyubiquitinated proteinsLeu-LeuProteolytic functionActive proteasomesPrimary proteaseProperties of cellsProteolytic systemProteasomeSpecific inhibitorMajor histocompatibility complexPhe-chloromethylketoneProteasome inhibitors
2000
The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses
Schwarz K, de Giuli R, Schmidtke G, Kostka S, van den Broek M, Kim K, Crews C, Kraft R, Groettrup M. The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses. The Journal Of Immunology 2000, 164: 6147-6157. PMID: 10843664, PMCID: PMC2507740, DOI: 10.4049/jimmunol.164.12.6147.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAmino Acid SequenceAnimalsAntigen PresentationAntigens, ViralApoptosisCell DivisionCell LineCysteine EndopeptidasesCysteine Proteinase InhibitorsDose-Response Relationship, ImmunologicDown-RegulationGlycoproteinsHumansHybridomasHydrolysisLymphocyte ActivationLymphocytic choriomeningitis virusMiceMice, Inbred BALB CMice, Inbred C57BLMolecular Sequence DataMultienzyme ComplexesNucleoproteinsOligopeptidesPeptide FragmentsProteasome Endopeptidase ComplexT-Lymphocytes, CytotoxicTumor Cells, CulturedUbiquitinsUp-RegulationViral ProteinsConceptsAg presentationProteasome inhibitor lactacystinCellular proliferationProteasome activitySelective inhibitionMHC class IDose-dependent mannerTransplant rejectionAutoimmune diseasesMouse CMVAntigen presentationMost MHC class INontoxic dosesChymotrypsin-like activityClass ISelective proteasome inhibitor lactacystinApoptosis inductionMicroM lactacystinViral proteinsPresentationInhibitionComplete inhibitionLactacystinVivoProliferation
1999
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity
Meng L, Mohan R, Kwok B, Elofsson M, Sin N, Crews C. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 1999, 96: 10403-10408. PMID: 10468620, PMCID: PMC17900, DOI: 10.1073/pnas.96.18.10403.Peer-Reviewed Original ResearchAnimalsAntibiotics, AntineoplasticAnti-Inflammatory Agents, Non-SteroidalCattleCells, CulturedCysteine EndopeptidasesCysteine Proteinase InhibitorsEndothelium, VascularErythrocytesHeLa CellsHumansKineticsMultienzyme ComplexesOligopeptidesProteasome Endopeptidase ComplexTumor Cells, CulturedTumor Suppressor Protein p53UbiquitinsUmbilical Veins