2024
Identification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies
Cosgun K, Robinson M, Agadzhanian N, Cheng Z, Oulghazi S, Berning P, Fonseca-Arce D, Kume K, Fontaine J, Chan L, Lee J, Yu F, Qian Z, Song J, Chan W, Chen J, Taketo M, Schjerven H, Müschen M. Identification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies. Blood 2024, 144: 4125-4125. DOI: 10.1182/blood-2024-208125.Peer-Reviewed Original ResearchProtein degradation pathwaysB-ALL cellsProtein degradationRepression of MYCTranscriptional activity of MYCCell deathAcute cell deathLoss of colony formationChIP-seq analysisActive enhancer marksB-cell malignanciesSuper-enhancer regionsActivation of MYCIkaros transcription factorB-lymphoid cellsCell linesB cell identityDefective protein degradationB-cateninNon-lymphoid cell linesDegradation pathwayMantle cell lymphomaProtein levelsB-ALLChIP-seqTargeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies
Cosgun K, Robinson M, Agadzhanian N, Berning P, Fonseca-Arce D, Leveille E, Kothari S, Davids M, Jellusova J, Müschen M. Targeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies. Blood 2024, 144: 1412. DOI: 10.1182/blood-2024-208598.Peer-Reviewed Original ResearchProtein degradationRepression of MYCTranscriptional repression of MYCTranscriptional repressionPromote survivalProteasome inhibitorsProtein degradation pathwaysCell typesN-terminal residuesInduce cell deathRefractory B-cell malignanciesB-cateninB-cell malignanciesRNAi screenInteractome studiesB cell selectionRepressive complexesGene dependenciesProteasomal degradationB cellsChemogenomic screensProteasome inhibitor bortezomibActivated mycDeletion of Ctnnb1Cell deathNext steps for targeted protein degradation
Krone M, Crews C. Next steps for targeted protein degradation. Cell Chemical Biology 2024, 32: 219-226. PMID: 39500325, DOI: 10.1016/j.chembiol.2024.10.004.Peer-Reviewed Original ResearchMethylarginine targeting chimeras for lysosomal degradation of intracellular proteins
Seabrook L, Franco C, Loy C, Osman J, Fredlender C, Zimak J, Campos M, Nguyen S, Watson R, Levine S, Khalil M, Sumigray K, Trader D, Albrecht L. Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins. Nature Chemical Biology 2024, 20: 1566-1576. PMID: 39414979, DOI: 10.1038/s41589-024-01741-y.Peer-Reviewed Original ResearchProtein arginine methyltransferasesTarget proteinsLoss-of-function phenotypesDegradation of intracellular proteinsUbiquitin-proteasome pathwayHistone deacetylase 6Bromodomain-containing protein 4Discovery of small moleculesTargeted protein degradationDegrade target proteinsTargeting chimerasArginine methylationArginine methyltransferasesProtein methylationPathogenic proteinsLysosomal deliveryLysosomal pathwayIntracellular proteinsLysosomal degradationHeterobifunctional small moleculesProtein degradationSmall-molecule degradersLysosomal proteolysisSubstrate degradationSmall moleculesHyd/UBR5 defines a tumor suppressor pathway that links Polycomb repressive complex to regulated protein degradation in tissue growth control and tumorigenesis
Wen P, Lei H, Deng H, Deng S, Tirado C, Wang M, Mu P, Zheng Y, Pan D. Hyd/UBR5 defines a tumor suppressor pathway that links Polycomb repressive complex to regulated protein degradation in tissue growth control and tumorigenesis. Genes & Development 2024, 38: 675-691. PMID: 39137945, PMCID: PMC11368183, DOI: 10.1101/gad.351856.124.Peer-Reviewed Original ResearchConceptsPolycomb Repressive Complex1Tumor suppressor pathwayTissue growth controlSuppressor pathwayProtein degradationZinc finger genesGrowth controlUbiquitin-mediated degradationE3 ubiquitin ligasePolycomb repressive complexesProtein degradation pathwaysTumor suppressor geneHyperplastic discsFinger genesMammalian homologSubstrate adaptorRepressive complexesUbiquitin ligaseEmbryonic segmentationProtein complexesModel organismsHuman geneticsUpstream regulatorSuppressor geneProstate cancer tumorigenesisBifunctional Molecules That Induce Both Targeted Degradation and Transcytosis of Extracellular Proteins in Brain Cells
Howell R, Wang S, Khambete M, McDonald D, Spiegel D. Bifunctional Molecules That Induce Both Targeted Degradation and Transcytosis of Extracellular Proteins in Brain Cells. Journal Of The American Chemical Society 2024, 146: 16404-16411. PMID: 38855935, DOI: 10.1021/jacs.3c13320.Peer-Reviewed Original ResearchLow-density lipoprotein receptor-related protein 1Targeted protein degradationTarget proteinsClathrin-mediated mechanismLipoprotein receptor-related protein 1Chloroalkane ligandTranscytosis of proteinsExtracellular proteinsPeptide motifsLysosomal localizationTargeted degradationHaloTag proteinCovalent taggingProtein degradationLysosomal proteolysisBlood-brain barrierProteinDegradable proteinCentral nervous systemProtein 1Bifunctional small moleculesEffective therapeutic strategyPrimary receptorTranscytosisStreptavidinMitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility
Ergun Y, Imamoglu A, Cozzolino M, Demirkiran C, Basar M, Garg A, Yildirim R, Seli E. Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility. International Journal Of Molecular Sciences 2024, 25: 1866. PMID: 38339144, PMCID: PMC10855406, DOI: 10.3390/ijms25031866.Peer-Reviewed Original ResearchConceptsCaseinolytic peptidase PMouse modelProtein homeostasisStress responseUnfolded protein stress responseProtein stress responseCumulus/granulosa cellsOocyte competenceOocyte functionGlobal deletionFunctional abnormalitiesGenes clpPMetabolic stress responseFemale subfertilityFemale infertilityOocyte-specificOocytesReproductive functionMtUPRMiceProtein degradationReproductive competenceFemale fertilityDeletionHomeostasisYeast 26S proteasome nuclear import is coupled to nucleus-specific degradation of the karyopherin adaptor protein Sts1
Breckel C, Johnson Z, Hickey C, Hochstrasser M. Yeast 26S proteasome nuclear import is coupled to nucleus-specific degradation of the karyopherin adaptor protein Sts1. Scientific Reports 2024, 14: 2048. PMID: 38267508, PMCID: PMC10808114, DOI: 10.1038/s41598-024-52352-5.Peer-Reviewed Original ResearchConceptsProteasome storage granulesNuclear importUbiquitin-independent proteasomal degradationProteasome degradation in vitroYeast Saccharomyces cerevisiaeProlonged glucose starvationNuclear import factorsUbiquitin-proteasome systemProteasome interactionGlucose starvationKaryopherin proteinsProteasomal degradationNuclear transportCellular homeostasisDegradation in vivoSTS1KaryopherinProtein degradationProteasomeDegradation in vitroGlucose refeedingStorage granulesProteinEukaryotesRanGTP
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 subunitDesign of a mucin-selective protease for targeted degradation of cancer-associated mucins
Pedram K, Shon D, Tender G, Mantuano N, Northey J, Metcalf K, Wisnovsky S, Riley N, Forcina G, Malaker S, Kuo A, George B, Miller C, Casey K, Vilches-Moure J, Ferracane M, Weaver V, Läubli H, Bertozzi C. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nature Biotechnology 2023, 42: 597-607. PMID: 37537499, PMCID: PMC11018308, DOI: 10.1038/s41587-023-01840-6.Peer-Reviewed Original ResearchCancer progressionSpecific protein glycoformsUndruggable proteinsTargeted degradationProtein degradationBreast cancer progressionCell surface bindingSubstrate selectivityCell-type selectivityCell deathGlycan motifsProtein glycoformsDiscrete peptidesCancer cellsProteinCulture modelProteaseTarget cellsTumor growthCancer-associated mucinsCellsMouse modelDegradersGrowthMotifA membrane-sensing mechanism links lipid metabolism to protein degradation at the nuclear envelope
Lee S, Rodrı́guez J, Merta H, Bahmanyar S. A membrane-sensing mechanism links lipid metabolism to protein degradation at the nuclear envelope. Journal Of Cell Biology 2023, 222: e202304026. PMID: 37382667, PMCID: PMC10309186, DOI: 10.1083/jcb.202304026.Peer-Reviewed Original ResearchConceptsAmphipathic helixDirect lipid-protein interactionsNuclear envelopeLipid-protein interactionsLipid compositionPhosphatidic acid phosphatase lipin-1INM proteomeNucleoplasmic domainOrganelle identityProteasomal regulationMembrane domainsAnimal cellsProteasomal degradationMaster regulatorProtein degradationLipid environmentLipin-1Packing defectsDAG speciesCTDNEP1Metabolism impactsSUN2Disease mechanismsMetabolismBroad implicationsDesign of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes
Zahid H, Costello J, Li Y, Kimbrough J, Actis M, Rankovic Z, Yan Q, Pomerantz W. Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes. ACS Chemical Biology 2023, 18: 1278-1293. PMID: 37260298, PMCID: PMC10698694, DOI: 10.1021/acschembio.2c00902.Peer-Reviewed Original ResearchConceptsChromatin Remodeling ComplexNon-BET bromodomainsRemodeling complexProtein degradationHeterobifunctional moleculesBET familyProtein targetsPyrimidine base analogsNumber of degradersDegradersOncogenic roleTernary complexExit vectorsWestern blottingProteinFirst exampleClass IChallenging targetComplexesCECR2ChromatinBromodomainsBPTFFamilyNanoBRETTumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease
Mansky R, Greguske E, Yu D, Zarate N, Intihar T, Tsai W, Brown T, Thayer M, Kumar K, Gomez-Pastor R. Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease. Cell Reports 2023, 42: 112198. PMID: 36867535, PMCID: PMC10128052, DOI: 10.1016/j.celrep.2023.112198.Peer-Reviewed Original ResearchConceptsMajor transcription factorTumor suppressor p53Huntington's diseaseHtt aggregationTranscription factorsE3 ligase MDM2Protein degradationSuppressor p53Reciprocal regulationMutant HttP53 stabilizationMolecular differencesCell proliferationHSF1Neurodegenerative diseasesP53Most cancersNeurodegenerationP53 deletionTranscriptionDegradationDeletionAbundanceHTT
2022
Proteotype coevolution and quantitative diversity across 11 mammalian species
Ba Q, Hei Y, Dighe A, Li W, Maziarz J, Pak I, Wang S, Wagner GP, Liu Y. Proteotype coevolution and quantitative diversity across 11 mammalian species. Science Advances 2022, 8: eabn0756. PMID: 36083897, PMCID: PMC9462687, DOI: 10.1126/sciadv.abn0756.Peer-Reviewed Original ResearchConceptsMammalian speciesRNA metabolic processesCommon mammalian speciesUbiquitin-proteasome systemEvolutionary profilingMammalian lineagesProteomic methodsProtein degradationProtein abundanceGene expressionProtein expression levelsHigh interspeciesMetabolic processesCovariation analysisFunctional roleNucleotide levelExpression levelsQuantitative diversityCoevolutionMammalsSpeciesRemarkable variationExpressionTranscriptomeBiological variabilityCombined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.
Ghosh S, Mazumdar T, Xu W, Powell RT, Stephan C, Shen L, Shah PA, Pickering CR, Myers JN, Wang J, Frederick MJ, Johnson FM. Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers. Clinical Cancer Research 2022, 28: 4479-4493. PMID: 35972731, PMCID: PMC9588713, DOI: 10.1158/1078-0432.ccr-22-1627.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAlphapapillomavirusApoptosisATPases Associated with Diverse Cellular ActivitiesAurora KinasesCell Cycle ProteinsFemaleHumansOncogene Proteins, ViralPapillomaviridaePapillomavirus E7 ProteinsPapillomavirus InfectionsRetinoblastoma ProteinUterine Cervical NeoplasmsConceptsHPV-positive cancer cellsInhibition-induced apoptosisAurora kinase inhibitorsAurora kinase inhibitionCancer cellsKinase inhibitionAbsence of RbViral oncoprotein E7Kinase inhibitorsMitotic exitAAA-ATPaseProtein degradationRb functionMechanisms of sensitivityPathway componentsTRIP13MAD2L1Extensive apoptosisCancer cell linesSquamous cancer cell linesApoptosisCell linesRetinoblastoma expressionBUB1BProtein expression correlatesPROTACs: past, present and future
Li K, Crews CM. PROTACs: past, present and future. Chemical Society Reviews 2022, 51: 5214-5236. PMID: 35671157, PMCID: PMC10237031, DOI: 10.1039/d2cs00193d.Peer-Reviewed Original ResearchConceptsProtein of interestProteolysis-targeting chimerasUbiquitin-proteasome systemE3 ubiquitin ligaseSmall molecule inhibitorsUbiquitin ligaseNonenzymatic functionProtein degradationHeterobifunctional moleculesDrug resistance mechanismsMolecule inhibitorsSubsequent degradationUbiquitinationLigasePromising therapeuticsProteinChimerasPotential toxicityDegradationMechanismHijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Nalawansha DA, Li K, Hines J, Crews CM. Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation. Journal Of The American Chemical Society 2022, 144: 5594-5605. PMID: 35311258, PMCID: PMC10331457, DOI: 10.1021/jacs.2c00874.Peer-Reviewed Original ResearchConceptsE3 ligase complexLigase complexProtein degradationReader proteinsMethyl readersE3 ligaseProteasomal degradationPROTAC designProtein levelsProteinLigand pairsDrug discovery paradigmPROTACsNatural mechanismGeneralizable approachComplexesDiscovery paradigmCUL4BRD2DegradationLigaseL3MBTL3FKBP12Biological evaluationPromising strategy
2021
Bifunctional small molecules that mediate the degradation of extracellular proteins
Caianiello DF, Zhang M, Ray JD, Howell RA, Swartzel JC, Branham EMJ, Chirkin E, Sabbasani VR, Gong AZ, McDonald DM, Muthusamy V, Spiegel DA. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nature Chemical Biology 2021, 17: 947-953. PMID: 34413525, DOI: 10.1038/s41589-021-00851-1.Peer-Reviewed Original ResearchConceptsExtracellular proteinsTarget proteinsUbiquitin-proteasome systemBifunctional small moleculesSynthetic moleculesProtein degradationIntracellular proteinsProinflammatory cytokine proteinProteinLysosomal proteasesTernary complexSmall moleculesPromising therapeutic strategyCytokine proteinsTherapeutic strategiesMoleculesDegradationProteaseDisease treatmentExperimental evidenceProteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation
Bond MJ, Crews CM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chemical Biology 2021, 2: 725-742. PMID: 34212149, PMCID: PMC8190915, DOI: 10.1039/d1cb00011j.Peer-Reviewed Original ResearchTargeted protein degradation: A promise for undruggable proteins
Samarasinghe KTG, Crews CM. Targeted protein degradation: A promise for undruggable proteins. Cell Chemical Biology 2021, 28: 934-951. PMID: 34004187, PMCID: PMC8286327, DOI: 10.1016/j.chembiol.2021.04.011.Peer-Reviewed Original ResearchConceptsProteolysis Targeting ChimerasUndruggable proteinsDisease-causing proteinsProtein degradation strategiesProteostasis mechanismsProtein homeostasisTranscription factorsProtein degradationHeterobifunctional moleculesProteinDegradation strategiesDisease initiationBiological effectsProteostasisDegradationPotential therapeutic modalityHomeostasisChimerasCellsAccumulation
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