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Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer

DC Field Value Language
dc.contributor.author김석준-
dc.contributor.author전경희-
dc.date.accessioned2017-02-24T03:36:11Z-
dc.date.available2017-02-24T03:36:11Z-
dc.date.issued2016-
dc.identifier.issn0950-9232-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/146388-
dc.description.abstractMutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.-
dc.description.statementOfResponsibilityrestriction-
dc.format.extent251~260-
dc.languageEnglish-
dc.publisherNature Publishing Group-
dc.relation.isPartOfONCOGENE-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHApoptosis/drug effects-
dc.subject.MESHApoptosis/genetics-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Nucleus/metabolism-
dc.subject.MESHCyclin B1/metabolism-
dc.subject.MESHFemale-
dc.subject.MESHG2 Phase Cell Cycle Checkpoints/drug effects-
dc.subject.MESHGene Expression Regulation, Neoplastic-
dc.subject.MESHHumans-
dc.subject.MESHMice, Inbred BALB C-
dc.subject.MESHOligopeptides/pharmacology-
dc.subject.MESHPTEN Phosphohydrolase/genetics-
dc.subject.MESHPTEN Phosphohydrolase/metabolism*-
dc.subject.MESHPhosphorylation-
dc.subject.MESHReceptor, Notch1/genetics-
dc.subject.MESHReceptor, Notch1/metabolism-
dc.subject.MESHReceptors, Notch/genetics-
dc.subject.MESHReceptors, Notch/metabolism*-
dc.subject.MESHSignal Transduction-
dc.subject.MESHStomach Neoplasms/drug therapy-
dc.subject.MESHStomach Neoplasms/metabolism*-
dc.subject.MESHStomach Neoplasms/mortality-
dc.subject.MESHStomach Neoplasms/pathology*-
dc.subject.MESHXenograft Model Antitumor Assays-
dc.titleActivation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer-
dc.typeArticle-
dc.publisher.locationEngland-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Biochemistry & Molecular Biology-
dc.contributor.googleauthorS-J Kim-
dc.contributor.googleauthorH-W Lee-
dc.contributor.googleauthorJ-H Baek-
dc.contributor.googleauthorY-H Cho-
dc.contributor.googleauthorHG Kang-
dc.contributor.googleauthorJS Jeong-
dc.contributor.googleauthorJ Song-
dc.contributor.googleauthorH-S Park-
dc.contributor.googleauthorK-H Chun-
dc.identifier.doi10.1038/onc.2015.80-
dc.contributor.localIdA00544-
dc.contributor.localIdA03501-
dc.relation.journalcodeJ02413-
dc.identifier.eissn1476-5594-
dc.identifier.pmid25823029-
dc.identifier.urlhttp://www.nature.com/onc/journal/v35/n2/full/onc201580a.html-
dc.contributor.alternativeNameKim, Seok Jun-
dc.contributor.alternativeNameChun, Kyung Hee-
dc.contributor.affiliatedAuthorKim, Seok Jun-
dc.contributor.affiliatedAuthorChun, Kyung Hee-
dc.citation.volume35-
dc.citation.number2-
dc.citation.startPage251-
dc.citation.endPage260-
dc.identifier.bibliographicCitationONCOGENE, Vol.35(2) : 251-260, 2016-
dc.date.modified2017-02-24-
dc.identifier.rimsid47896-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers

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