2019
WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, Gonzalez A, McPartlan JS, Li T, Zhang Y, Bin Liu J, Lazaro JB, Gu P, Piett CG, Apffel A, Ali SO, Deasy R, Keskula P, Ng RWS, Roberts EA, Reznichenko E, Leung L, Alimova M, Schenone M, Islam M, Maruvka YE, Liu Y, Roper J, Raghavan S, Giannakis M, Tseng YY, Nagel ZD, D’Andrea A, Root DE, Boehm JS, Getz G, Chang S, Golub TR, Tsherniak A, Vazquez F, Bass AJ. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 2019, 568: 551-556. PMID: 30971823, PMCID: PMC6580861, DOI: 10.1038/s41586-019-1102-x.Peer-Reviewed Original ResearchConceptsSynthetic lethal targetLethal targetGenetic eventsDepletion of WRNCRISPR-Cas9-mediated knockoutDNA repair pathwaysDNA repair processesSynthetic lethal relationshipSynthetic lethal vulnerabilitiesDNA repair defectsDNA mismatch repairCell cycle arrestWRN helicaseHelicase activityPromising drug targetHomologous recombinationRepair pathwaysRNA interferenceDNA breaksSynthetic lethalityWRNLethal relationshipExonuclease activityRepair defectsMismatch repair
2016
Dysfunctional telomeres induce p53‐dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation
Wang Y, Wang X, Flores ER, Yu J, Chang S. Dysfunctional telomeres induce p53‐dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 2016, 15: 646-660. PMID: 27113195, PMCID: PMC4933665, DOI: 10.1111/acel.12476.Peer-Reviewed Original Research
2014
Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A
Gupta R, Dong Y, Solomon PD, Wettersten HI, Cheng CJ, Min JN, Henson J, Dogra SK, Hwang SH, Hammock BD, Zhu LJ, Reddel RR, Saltzman WM, Weiss RH, Chang S, Green MR, Wajapeyee N. Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: e3062-e3071. PMID: 25024194, PMCID: PMC4121806, DOI: 10.1073/pnas.1411370111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Line, TumorCyclin-Dependent Kinase Inhibitor p21HumansMiceMice, NudeMutationNeoplasms, ExperimentalTelomeraseTumor Suppressor Protein p53ConceptsP53-mediated transcriptional activationCyclin-dependent kinase inhibitor 1AMutant p53Telomerase inhibitionTumor suppressor p53Transcriptional activationSynergistic tumor suppressionTelomere dysfunctionCheckpoint proteinsP53 upregulated modulatorTumor suppressionCDK inhibitorsSuppressor p53Inhibitor 1AP53 activityTelomeraseHuman cancersCancer cell linesApoptosis inductionPharmacological inhibitionApoptosisCell linesPharmacological restorationP21Growth inhibition
2013
p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
Wang Y, Sharpless N, Chang S. p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses. Journal Of Clinical Investigation 2013, 123: 4489-4501. PMID: 24091330, PMCID: PMC3784543, DOI: 10.1172/jci69574.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsApoptosisAtaxia Telangiectasia Mutated ProteinsBone Marrow TransplantationCell ProliferationCells, CulturedCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p21DNA DamageDNA RepairDNA-Binding ProteinsFemaleHematopoiesisHematopoietic Stem CellsIntestine, SmallMaleMiceMice, SCIDMice, TransgenicProtein StabilitySequence DeletionSpleenTelomereTelomere HomeostasisTumor Suppressor Protein p53ConceptsHematopoietic cellsDeletion of p21P21-dependent cell cycle arrestOrgan impairmentTelomere dysfunctionCell cycle arrestMouse modelDNA damage responseSmall intestineFunctional defectsCell functionProliferative capacityP53-dependent apoptosisCycle arrestDysfunctional telomeresCellular senescenceDysfunctionP53-dependent DNA damage responseProliferative cellsHematopoietic systemProtective functionTumor suppressorProliferative defectP53 stabilizationCellsThe mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability
Min JN, Tian Y, Xiao Y, Wu L, Li L, Chang S. The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability. Cell Research 2013, 23: 1396-1413. PMID: 23979016, PMCID: PMC3847565, DOI: 10.1038/cr.2013.113.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsCells, CulturedCellular SenescenceChromatinChromatin Assembly and DisassemblyDNA Breaks, Double-StrandedDNA HelicasesDNA RepairDNA ReplicationFibroblastsGenomic InstabilityHydroxyureaMiceMice, Inbred C57BLMice, KnockoutMutationNucleic Acid Synthesis InhibitorsTelomereTumor Suppressor Protein p53ConceptsHomology-directed DNA repairEfficient telomere replicationGenome stabilityTelomere replicationDependent DNA damage responseDNA double-strand breaksDNA damage responseDNA damage fociMammalian cell linesATPase catalytic subunitConditional knockout approachDouble-strand breaksINO80 chromatinChromatin remodelingOrganismal functionTranscriptional regulationFragile telomeresDamage responseDNA replicationCatalytic subunitDamage fociDysfunctional telomeresSingle-strand DNADNA repairKnockout approach
2012
Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis
Akbay EA, Peña CG, Ruder D, Michel JA, Nakada Y, Pathak S, Multani AS, Chang S, Castrillon DH. Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis. Oncogene 2012, 32: 2211-2219. PMID: 22689059, PMCID: PMC3636499, DOI: 10.1038/onc.2012.232.Peer-Reviewed Original ResearchMeSH KeywordsAneuploidyAnimalsCarcinoma, EndometrioidCell Transformation, NeoplasticDisease Models, AnimalDNA Breaks, Double-StrandedDNA-Binding ProteinsEndometrial NeoplasmsFemaleHumansMiceMice, TransgenicShelterin ComplexTelomere HomeostasisTelomere-Binding ProteinsTumor Cells, CulturedTumor Suppressor Protein p53ConceptsType II endometrial cancerEndometrial intraepithelial carcinomaEndometrial cancerEndometrial adenocarcinomaEndometrial carcinogenesisTelomerase-null miceProminent nuclear atypiaType II tumorsMulti-organ failureType II cancersInvasive endometrial adenocarcinomaMonths of ageMetastatic diseaseII tumorsEndometrial lesionsIntraepithelial carcinomaEndometrial epitheliumNuclear atypiaTumorsAdenocarcinomaVivo correlatesDetectable DNA damageHuman tumorsMiceLesions
2011
Essential roles for Pot1b in HSC self-renewal and survival
Wang Y, Shen MF, Chang S. Essential roles for Pot1b in HSC self-renewal and survival. Blood 2011, 118: 6068-6077. PMID: 21948176, PMCID: PMC3234665, DOI: 10.1182/blood-2011-06-361527.Peer-Reviewed Original ResearchAgingAnemia, AplasticAnimalsApoptosisBone Marrow CellsBone Marrow DiseasesBone Marrow Failure DisordersCell DifferentiationCell SurvivalCells, CulturedChromosomes, MammalianDNA DamageDNA-Binding ProteinsFemaleHematopoietic Stem CellsHemoglobinuria, ParoxysmalMaleMiceMice, Inbred ICRMice, Mutant StrainsMice, SCIDTelomereTumor Suppressor Protein p53
2010
The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development
Akhter S, Lam YC, Chang S, Legerski RJ. The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development. Aging Cell 2010, 9: 1047-1056. PMID: 20854421, PMCID: PMC3719988, DOI: 10.1111/j.1474-9726.2010.00631.x.Peer-Reviewed Original ResearchConceptsMutant mouse embryonic fibroblastsSNM1B/ApolloCell proliferation defectMouse embryonic fibroblastsNormal cell proliferationDevelopmental failureHomozygous null miceEnd fusionsProliferation defectEmbryonic developmentGenomic instabilityEmbryonic fibroblastsTelomeric endDevelopmental defectsCell deathVivo roleCell proliferationImpaired proliferationTelomeresNull miceMutant mice
2008
Critical and Distinct Roles of p16 and Telomerase in Regulating the Proliferative Life Span of Normal Human Prostate Epithelial Progenitor Cells*
Bhatia B, Jiang M, Suraneni M, Patrawala L, Badeaux M, Schneider-Broussard R, Multani AS, Jeter CR, Calhoun-Davis T, Hu L, Hu J, Tsavachidis S, Zhang W, Chang S, Hayward SW, Tang DG. Critical and Distinct Roles of p16 and Telomerase in Regulating the Proliferative Life Span of Normal Human Prostate Epithelial Progenitor Cells*. Journal Of Biological Chemistry 2008, 283: 27957-27972. PMID: 18662989, PMCID: PMC2562067, DOI: 10.1074/jbc.m803467200.Peer-Reviewed Original ResearchConceptsProliferative life spanNHP cellsMolecular mechanismsProgenitor cellsSuppression of p16Normal human prostate epithelial cellsGene expression profilesLife spanProstate epithelial progenitor cellsHuman prostate epithelial cellsRegulation of p16Activation of p53Prostate epithelial cellsEpithelial progenitor cellsCell proliferative capacityExpression profilesBasal-like cellsProgenitor markersMultilineage differentiationTelomerase expressionDistinct rolesCell life spanCell marker CD44P16 inhibitionEpithelial cellsTelomere dysfunction and tumour suppression: the senescence connection
Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nature Reviews Cancer 2008, 8: 450-458. PMID: 18500246, PMCID: PMC3688269, DOI: 10.1038/nrc2393.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCellular SenescenceCyclin-Dependent Kinase Inhibitor p21DNA DamageHumansNeoplasmsRetinoblastoma ProteinTelomeraseTelomereTumor Suppressor Protein p53ConceptsTelomere dysfunctionDysfunctional telomeresDNA damage responseKey PointsTelomeresEukaryotic chromosomesGenome instabilityShelterin complexApoptotic programDamage responseRepetitive sequencesCellular senescenceTelomeric endTumor suppressionProtein resultsP53 pathwayMutant p53TelomeresSpontaneous tumorigenesisSenescenceTumorigenesisMouse modelChromosomesDysfunctionProteinApoptosisDual roles of telomere dysfunction in initiation and suppression of tumorigenesis
Cosme-Blanco W, Chang S. Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis. Experimental Cell Research 2008, 314: 1973-1979. PMID: 18448098, PMCID: PMC3690559, DOI: 10.1016/j.yexcr.2008.03.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDNA DamageHumansNeoplasmsPrecancerous ConditionsTelomeraseTelomereTumor Suppressor Protein p53ConceptsDNA double-strand breaksDysfunctional telomeresGenomic instabilityPotent tumor suppressor mechanismTumorigenic potentialSimple repeat sequencesTumor suppressor mechanismDouble-strand breaksCell tumorigenic potentialSuppression of tumorigenesisCancer cellsChromosomal endsTelomere dysfunctionCellular senescenceRepeat sequencesGenetic changesTelomeresGenetic lesionsP53 pathwayTumor initiationDicentric chromosomesSuppressor mechanismIntact p53 pathwayHuman carcinomasRare cellsEvidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT
Bhatia B, Multani AS, Patrawala L, Chen X, Calhoun‐Davis T, Zhou J, Schroeder L, Schneider‐Broussard R, Shen J, Pathak S, Chang S, Tang DG. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. International Journal Of Cancer 2008, 122: 1483-1495. PMID: 18059027, DOI: 10.1002/ijc.23222.Peer-Reviewed Original ResearchConceptsHuman prostate epithelial cellsNHP cellsProstate epithelial cellsCell fusionVivo tumorigenicityTumor cellsTumor developmentNormal human prostate epithelial cellsEpithelial cellsAR mRNA expressionCell-cell fusionProstate cancer cell linesPotential mechanismsGene expression analysisP16INK4a protein expressionModel cell systemGenomic stabilityLNCaP prostate cancerCancer cell linesExogenous p16Expression analysisProstate cancerSenescent fibroblastsProgenitor markersProstate tumorigenesis
2007
Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway
Akli S, Van Pelt CS, Bui T, Multani AS, Chang S, Johnson D, Tucker S, Keyomarsi K. Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 Pathway. Cancer Research 2007, 67: 7212-7222. PMID: 17671189, DOI: 10.1158/0008-5472.can-07-0599.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAnimalsApoptosisBlotting, WesternCyclin ECyclin-Dependent Kinase Inhibitor p16FemaleGene Expression Regulation, NeoplasticGene SilencingHumansImmunoenzyme TechniquesIn Situ Nick-End LabelingLoss of HeterozygosityLung NeoplasmsMammary Neoplasms, ExperimentalMiceMice, KnockoutMice, TransgenicMutationPolymerase Chain ReactionTumor Cells, CulturedTumor Suppressor Protein p53ConceptsFull-length cyclin ECyclin E overexpressionCyclin EARF-p53 pathwayTransgenic miceLow molecular weight cyclin EE overexpressionMetastatic mammary carcinomaMammary tumor formationWeight cyclin ETumor-bearing animalsBreast cancer tumorigenesisBreast cancer cellsMouse mammary tumor virus promoterLow molecular weight isoformsLMW formsOncologic roleInactivation of p53Mammary carcinomaBreast cancerMammary adenocarcinomaLoss of heterozygosityCancer tumorigenesisMammary epithelial cellsMolecular weight isoformsTelomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence
Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence. EMBO Reports 2007, 8: 497-503. PMID: 17396137, PMCID: PMC1866197, DOI: 10.1038/sj.embor.7400937.Peer-Reviewed Original ResearchMeSH Keywords9,10-Dimethyl-1,2-benzanthraceneAnimalsApoptosisCellular SenescenceEmbryo, MammalianFibroblastsMicePapillomaSkin NeoplasmsTelomereTumor Suppressor Protein p53ConceptsP53-dependent cellular senescenceSpontaneous tumorigenesisCellular senescenceCellular senescence pathwaysSenescence pathwaysCell cycle arrestSkin carcinomasSenescence markersTumorigenesisMiceDysfunctional telomeresTumor suppressionTelomere dysfunctionP53ApoptosisVivoSuppressionCarcinomaDysfunctionPathwaySenescence
2006
POT1b protects telomeres from end‐to‐end chromosomal fusions and aberrant homologous recombination
He H, Multani AS, Cosme‐Blanco W, Tahara H, Ma J, Pathak S, Deng Y, Chang S. POT1b protects telomeres from end‐to‐end chromosomal fusions and aberrant homologous recombination. The EMBO Journal 2006, 25: 5180-5190. PMID: 17053789, PMCID: PMC1630418, DOI: 10.1038/sj.emboj.7601294.Peer-Reviewed Original ResearchBlock of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations
Haines BB, Ryu CJ, Chang S, Protopopov A, Luch A, Kang YH, Draganov DD, Fragoso MF, Paik SG, Hong HJ, DePinho RA, Chen J. Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. Cancer Cell 2006, 9: 109-120. PMID: 16473278, DOI: 10.1016/j.ccr.2006.01.004.Peer-Reviewed Original Research
2005
Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005, 7: 469-483. PMID: 15894267, DOI: 10.1016/j.ccr.2005.04.023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCadherinsCarcinoma, Pancreatic DuctalCentrosomeChromosomal InstabilityChromosome AberrationsCytogenetic AnalysisDisease ProgressionGene ExpressionGene Expression RegulationGene RearrangementGenes, Tumor SuppressorHomeodomain ProteinsIntegrasesMiceMice, Inbred C57BLMice, Inbred StrainsMice, Mutant StrainsMice, TransgenicMutation, MissenseNeoplasm MetastasisOncogene Proteins v-erbBProto-Oncogene Proteins p21(ras)Ras ProteinsSurvival AnalysisTelomereTrans-ActivatorsTranslocation, GeneticTumor Suppressor Protein p53ConceptsPancreatic ductal adenocarcinomaTumor suppressor gene pathwaysDistinct genetic pathwaysGenetic requirementsGenetic pathwaysGenomic instabilityGene pathwaysChromosomal instabilityEndogenous expressionHuman diseasesNonreciprocal translocationsDuctal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaHuman carcinomasDisease pathogenesisMouse pancreasDifferent biological behaviorPathwayMetastatic carcinomaPrimary carcinomaTreatment strategiesCarcinomaBiological behaviorDevelopment of detectionTranslocation
2004
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
Tuveson D, Shaw A, Willis N, Silver D, Jackson E, Chang S, Mercer K, Grochow R, Hock H, Crowley D, Hingorani S, Zaks T, King C, Jacobetz M, Wang L, Bronson R, Orkin S, DePinho R, Jacks T. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 2004, 5: 375-387. PMID: 15093544, DOI: 10.1016/s1535-6108(04)00085-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell CycleCell DivisionCell Transformation, NeoplasticCellular SenescenceCongenital AbnormalitiesCrosses, GeneticCyclin-Dependent Kinase Inhibitor p16Embryo, MammalianFemaleFibroblastsGene Expression Regulation, DevelopmentalGenes, rasIntegrasesMaleMiceMice, Inbred C57BLMice, TransgenicMutationNeoplasmsStem CellsTumor Suppressor Protein p14ARFTumor Suppressor Protein p53Viral ProteinsConceptsCanonical Ras effectorRas effectorsOncogenic RasEmbryonic developmentAbnormal cellular proliferationDevelopmental defectsRas oncogeneGenetic lesionsConditional expressionWidespread expressionK-RasG12DCellular proliferationFurther genetic abnormalitiesEnhanced proliferationOncogeneProliferationExpressionGenetic abnormalitiesEffectorsMutationsAllelesRegulationPathwayFibroblastsFrank malignancy