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NADPH Oxidase 1 Activity and ROS Generation Are Regulated by Grb2/Cbl-Mediated Proteasomal Degradation of NoxO1 in Colon Cancer Cells

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dc.contributor.author박철근-
dc.contributor.author김호근-
dc.date.accessioned2021-02-03T08:01:25Z-
dc.date.available2021-02-03T08:01:25Z-
dc.date.issued2016-02-
dc.identifier.issn0008-5472-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/181604-
dc.description.abstractThe generation of reactive oxygen species (ROS) is required for proper cell signaling, but must be tightly regulated to minimize deleterious oxidizing effects. Activation of the NADPH oxidases (Nox) triggers ROS production and, thus, regulatory mechanisms exist to properly control Nox activity. In this study, we report a novel mechanism in which Nox1 activity is regulated through the proteasomal degradation of Nox organizer 1 (NoxO1). We found that through the interaction between NoxO1 and growth receptor-bound protein 2 (Grb2), the Casitas B-lineage lymphoma (Cbl) E3 ligase was recruited, leading to decreased NoxO1 stability and a subsequent reduction in ROS generation upon epidermal growth factor (EGF) stimulation. Additionally, we show that EGF-mediated phosphorylation of NoxO1 induced its release from Grb2 and facilitated its association with Nox activator 1 (NoxA1) to stimulate ROS production. Consistently, overexpression of Grb2 resulted in decreased Nox1 activity, whereas knockdown of Grb2 led to increased Nox1 activity in response to EGF. CRISPR/Cas9-mediated NoxO1 knockout in human colon cancer cells abrogated anchorage-independent growth on soft agar and tumor-forming ability in athymic nude mice. Moreover, the expression and stability of NoxO1 were significantly increased in human colon cancer tissues compared with normal colon. Taken together, these results support a model whereby Nox1 activity and ROS generation are regulated by Grb2/Cbl-mediated proteolysis of NoxO1 in response to EGF, providing new insight into the processes by which excessive ROS production may promote oncogenic signaling to drive colorectal tumorigenesis.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherAmerican Association for Cancer Research-
dc.relation.isPartOfCANCER RESEARCH-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHAnimals-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHColonic Neoplasms / genetics*-
dc.subject.MESHColonic Neoplasms / metabolism-
dc.subject.MESHGRB2 Adaptor Protein / genetics*-
dc.subject.MESHHumans-
dc.subject.MESHMice-
dc.subject.MESHNADH, NADPH Oxidoreductases / genetics-
dc.subject.MESHNADH, NADPH Oxidoreductases / metabolism*-
dc.subject.MESHNADPH Oxidase 1-
dc.subject.MESHReactive Oxygen Species-
dc.subject.MESHSignal Transduction-
dc.subject.MESHTransfection-
dc.titleNADPH Oxidase 1 Activity and ROS Generation Are Regulated by Grb2/Cbl-Mediated Proteasomal Degradation of NoxO1 in Colon Cancer Cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Pathology (병리학교실)-
dc.contributor.googleauthorJung Hee Joo-
dc.contributor.googleauthorHyunjin Oh-
dc.contributor.googleauthorMyungjin Kim-
dc.contributor.googleauthorEun Jung An-
dc.contributor.googleauthorRae-Kwon Kim-
dc.contributor.googleauthorSo-Young Lee-
dc.contributor.googleauthorDong Hoon Kang-
dc.contributor.googleauthorSang Won Kang-
dc.contributor.googleauthorCheol Keun Park-
dc.contributor.googleauthorHoguen Kim-
dc.contributor.googleauthorSu-Jae Lee-
dc.contributor.googleauthorDaekee Lee-
dc.contributor.googleauthorJae Hong Seol-
dc.contributor.googleauthorYun Soo Bae-
dc.identifier.doi10.1158/0008-5472.CAN-15-1512-
dc.contributor.localIdA05244-
dc.contributor.localIdA01183-
dc.contributor.localIdA01183-
dc.relation.journalcodeJ00452-
dc.identifier.eissn1538-7445-
dc.identifier.pmid26781991-
dc.contributor.alternativeNamePark, Cheol Keun-
dc.contributor.affiliatedAuthor박철근-
dc.contributor.affiliatedAuthor김호근-
dc.contributor.affiliatedAuthor김호근-
dc.citation.volume76-
dc.citation.number4-
dc.citation.startPage855-
dc.citation.endPage865-
dc.identifier.bibliographicCitationCANCER RESEARCH, Vol.76(4) : 855-865, 2016-02-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers

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