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MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors

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dc.contributor.author김재훈-
dc.contributor.author조한별-
dc.date.accessioned2021-04-29T17:30:04Z-
dc.date.available2021-04-29T17:30:04Z-
dc.date.issued2021-01-
dc.identifier.issn1553-7366-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/182371-
dc.description.abstractIntracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherPublic Library of Science-
dc.relation.isPartOfPLOS PATHOGENS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleMEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Obstetrics and Gynecology (산부인과학교실)-
dc.contributor.googleauthorAdrian J Luna-
dc.contributor.googleauthorRosa T Sterk-
dc.contributor.googleauthorAnastacia M Griego-Fisher-
dc.contributor.googleauthorJoon-Yong Chung-
dc.contributor.googleauthorKiersten L Berggren-
dc.contributor.googleauthorVirginie Bondu-
dc.contributor.googleauthorPamela Barraza-Flores-
dc.contributor.googleauthorAndrew T Cowan-
dc.contributor.googleauthorGregory N Gan-
dc.contributor.googleauthorEmrullah Yilmaz-
dc.contributor.googleauthorHanbyoul Cho-
dc.contributor.googleauthorJae-Hoon Kim-
dc.contributor.googleauthorStephen M Hewitt-
dc.contributor.googleauthorJulie E Bauman-
dc.contributor.googleauthorMichelle A Ozbun-
dc.identifier.doi10.1371/journal.ppat.1009216-
dc.contributor.localIdA00876-
dc.contributor.localIdA03921-
dc.relation.journalcodeJ02541-
dc.identifier.eissn1553-7374-
dc.identifier.pmid33481911-
dc.contributor.alternativeNameKim, Jae Hoon-
dc.contributor.affiliatedAuthor김재훈-
dc.contributor.affiliatedAuthor조한별-
dc.citation.volume17-
dc.citation.number1-
dc.citation.startPagee1009216-
dc.identifier.bibliographicCitationPLOS PATHOGENS, Vol.17(1) : e1009216, 2021-01-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Obstetrics and Gynecology (산부인과학교실) > 1. Journal Papers

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