2022
mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay
van den Elzen A, Watson M, Thoreen C. mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay. PLOS Genetics 2022, 18: e1010532. PMID: 36441824, PMCID: PMC9731452, DOI: 10.1371/journal.pgen.1010532.Peer-Reviewed Original ResearchConceptsTerminal sequenceGene expressionKey post-transcriptional regulatorsTerminal oligopyrimidine motifsCore promoter motifsPost-transcriptional regulatorsPromoter motifsMRNA decayTranslation initiationRegulatory sequencesReporter mRNAEfficient transcriptionLibrary sequencesEndogenous mRNARegulatory potentialNative mRNAHuman cellsTranscriptionMRNAHybrid sequencesSequenceExpressionMotifMRNA expressionTranslation
2017
La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region
Philippe L, Vasseur JJ, Debart F, Thoreen CC. La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region. Nucleic Acids Research 2017, 46: gkx1237-. PMID: 29244122, PMCID: PMC5814973, DOI: 10.1093/nar/gkx1237.Peer-Reviewed Original ResearchMeSH KeywordsAutoantigensBase SequenceBinding SitesBinding, CompetitiveCell-Free SystemComputational BiologyEukaryotic Initiation Factor-4FGene Expression RegulationHEK293 CellsHumansMechanistic Target of Rapamycin Complex 1Models, GeneticPolyribosomesProtein BindingProtein BiosynthesisProtein Interaction Domains and MotifsPyrimidinesRibonucleoproteinsRNA, MessengerConceptsTOP mRNA translationAdjacent regulatory regionsMRNA translationCap-binding domainCap structureRegulatory regionsEukaryotic initiation factor 4FMRNA 5' cap structureIntrinsic repressive activityTerminal oligopyrimidine motifsInitiation factor 4FMRNA 5' endsC-terminal halfGrowth-related mRNAsTOP mRNAsRepressive activityTranslation factorsMRNA targetsCoordinated changesGene expressionLARP1Cell growthProtein 1Top sequenceMRNAmTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4
Park Y, Reyna-Neyra A, Philippe L, Thoreen CC. mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4. Cell Reports 2017, 19: 1083-1090. PMID: 28494858, PMCID: PMC5811220, DOI: 10.1016/j.celrep.2017.04.042.Peer-Reviewed Original ResearchConceptsUpstream open reading framesATF4 translationTranscriptional programsProtein synthesisEukaryotic initiation factor 2 alphaInitiation factor 2 alphaPost-transcriptional controlRapamycin complex 1Open reading frameIntegrated stress responseAmino acid transportersTranscription factor 4Translation machineryTranslation repressorProtein familyReading frameMaster regulatorPromoter elementsBioinformatics analysisResponsive mRNAsAmino acid supplyStress responseMetabolic enzymesKey effectorsAcid transporters
2016
ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP
Muranen T, Selfors L, Hwang J, Gallegos L, Coloff J, Thoreen C, Kang S, Sabatini D, Mills G, Brugge J. ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP. Cancer Research 2016, 76: 7168-7180. PMID: 27913436, PMCID: PMC5161652, DOI: 10.1158/0008-5472.can-16-0155.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsBlotting, WesternCell Line, TumorCell ProliferationDrug Resistance, NeoplasmExtracellular Signal-Regulated MAP KinasesFemaleFluorescent Antibody TechniqueHeterograftsHumansMAP Kinase Signaling SystemMiceMice, Inbred NODMicroscopy, ConfocalNeoplasms, ExperimentalP38 Mitogen-Activated Protein KinasesPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsProtein Kinase InhibitorsProto-Oncogene MasProto-Oncogene Proteins c-mycSignal TransductionTOR Serine-Threonine KinasesTranscription FactorsYAP-Signaling ProteinsConceptsPI3K/mTOR inhibitorMTOR inhibitorsTumor cellsPI3K/mTOR pathwayCell-targeted therapiesTranscriptional regulator c-MycPI3K/mTORAnimal tumor modelsUpregulation of MYCChronic inhibitionInhibition of p38Cellular signaling mechanismsTumor growthMTOR pathwayTumor modelAberrant activationTherapyStress kinase p38C-MycKinase p38InhibitionConstitutive ERK activityAttractive targetContext-dependent mechanismsProliferation arrest
2012
A unifying model for mTORC1-mediated regulation of mRNA translation
Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 2012, 485: 109-113. PMID: 22552098, PMCID: PMC3347774, DOI: 10.1038/nature11083.Peer-Reviewed Original Research5' Untranslated RegionsAnimalsBase SequenceCell Line, TumorEukaryotic Initiation Factor-4EEukaryotic Initiation Factor-4GGene Expression RegulationHumansMaleMechanistic Target of Rapamycin Complex 1MiceModels, BiologicalMultiprotein ComplexesNaphthyridinesNucleotide MotifsPhosphorylationProstatic NeoplasmsProtein BindingProtein BiosynthesisProteinsRibosomesRNA, MessengerTOR Serine-Threonine Kinases
2006
mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s
Frias M, Thoreen C, Jaffe J, Schroder W, Sculley T, Carr S, Sabatini D. mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s. Current Biology 2006, 16: 1865-1870. PMID: 16919458, DOI: 10.1016/j.cub.2006.08.001.Peer-Reviewed Original ResearchConceptsAkt/PKBSerine/threonine kinaseAkt/PKB phosphorylationDistinct multiprotein complexesAssembly of mTORC2Multiprotein complexesThreonine kinaseAlternative splicingPKB phosphorylationMTORC2PKBMammalian targetCell growthMSin1KinaseIsoformsImportant roleSplicingComplexesPhosphorylationRapamycinProteinDifferent signalsRegulationMetabolism
2004
Huntingtin aggregates ask to be eaten
Thoreen C, Sabatini D. Huntingtin aggregates ask to be eaten. Nature Genetics 2004, 36: 553-554. PMID: 15167929, DOI: 10.1038/ng0604-553.Peer-Reviewed Original Research
2001
Integration of cytogenetic landmarks into the draft sequence of the human genome
BAC Resource Consortium T, Cheung V, Nowak N, Jang W, Kirsch I, Zhao S, Chen X, Furey T, Kim U, Kuo W, Olivier M, Conroy J, Kasprzyk A, Massa H, Yonescu R, Sait S, Thoreen C, Snijders A, Lemyre E, Bailey J, Bruzel A, Burrill W, Clegg S, Collins S, Dhami P, Friedman C, Han C, Herrick S, Lee J, Ligon A, Lowry S, Morley M, Narasimhan S, Osoegawa K, Peng Z, Plajzer-Frick I, Quade B, Scott D, Sirotkin K, Thorpe A, Gray J, Hudson J, Pinkel D, Ried T, Rowen L, Shen-Ong G, Strausberg R, Birney E, Callen D, Cheng J, Cox D, Doggett N, Carter N, Eichler E, Haussler D, Korenberg J, Morton C, Albertson D, Schuler G, de Jong P, Trask B. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 2001, 409: 953-958. PMID: 11237021, PMCID: PMC7845515, DOI: 10.1038/35057192.Peer-Reviewed Original ResearchConceptsHuman genomeDraft sequenceLarge-scale chromatin structureHuman diseasesGenome-wide setLarge-scale duplicationsEvolution of chromosomesCharacterization of genesFirst comprehensive integrationLarge-insert clonesGross chromosomal aberrationsChromatin structureCytogenetic landmarksGene familyRadiation hybridsSequence tagsGenomic sequencesSequence assemblyMolecular basisGenomeSequence differencesFunctional analysisSequence mapsSitu hybridizationChromosomes