E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis

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dc.contributor.authorKyeong Su Park-
dc.contributor.authorJu Hee Kim-
dc.contributor.authorHee Won Shin-
dc.contributor.authorKyung-Sook Chung-
dc.contributor.authorDong-Soo Im-
dc.contributor.authorJung Hwa Lim-
dc.contributor.authorCho Rok Jung-
dc.date.accessioned2017-04-19T10:13:33Z-
dc.date.available2017-04-19T10:13:33Z-
dc.date.issued2015-
dc.identifier.issn14712407-
dc.identifier.uri10.1186/s12885-015-1786-8ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/12921-
dc.description.abstractBackground: Missense mutation of VHL gene is frequently detected in type 2 VHL diseases and linked to a wide range of pVHL functions and stability. Certain mutant pVHLs retain ability to regulate HIFs but lose their function by instability. In this case, regulating of degradation of mutant pVHLs, can be postulated as therapeutic method. Method: The stability and cellular function of missense mutant pVHLs were determine in HEK293T transient expressing cell and 786-O stable cell line. Ubiquitination assay of mutant VHL proteins was performed in vitro system. Anticacner effect of adenovirus mediated shUCP expressing was evaluated using ex vivo mouse xenograft assay. Results: Three VHL missense mutants (V155A, L158Q, and Q164R) are directly ubiquitinated by E2-EPF UCP (UCP) in vitro. Mutant pVHLs are more unstable than wild type in cell. Missense mutant pVHLs interact with UCP directly in both in vitro and cellular systems. Lacking all of lysine residues of pVHL result in resistance to ubiquitination thereby increase its stability. Missense mutant pVHLs maintained the function of E3 ligase to ubiquitinate HIF-1aα in vitro. In cells expressing mutant pVHLs, Glut-1 and VEGF were relatively upregulated compared to their levels in cells expressing wild-type. Depletion of UCP restored missense mutant pVHLs levels and inhibited cell growth. Adenovirus-mediated shUCP RNA delivery inhibited tumor growth in ex vivo mouse xenograft model. Conclusion: These data suggest that targeting of UCP can be one of therapeutic method in type 2 VHL disease caused by unstable but functional missense mutant pVHL.-
dc.publisherSpringer-BMC-
dc.titleE2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis-
dc.title.alternativeE2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis-
dc.typeArticle-
dc.citation.titleBMC Cancer-
dc.citation.number0-
dc.citation.endPage800-
dc.citation.startPage800-
dc.citation.volume15-
dc.contributor.affiliatedAuthorKyung-Sook Chung-
dc.contributor.affiliatedAuthorJung Hwa Lim-
dc.contributor.affiliatedAuthorCho Rok Jung-
dc.contributor.alternativeName박경수-
dc.contributor.alternativeName김주희-
dc.contributor.alternativeName신희원-
dc.contributor.alternativeName정경숙-
dc.contributor.alternativeName임동수-
dc.contributor.alternativeName임정화-
dc.contributor.alternativeName정초록-
dc.identifier.bibliographicCitationBMC Cancer, vol. 15, pp. 800-800-
dc.identifier.doi10.1186/s12885-015-1786-8-
dc.subject.keywordE2-EPF UCP-
dc.subject.keywordProtein instability-
dc.subject.keywordpVHL missense mutation-
dc.subject.keywordUbiquitination-
dc.subject.keywordVHL disease-
dc.subject.localE2-EPF UCP-
dc.subject.localProtein instability-
dc.subject.localpVHL missense mutation-
dc.subject.localUbiquitination-
dc.subject.localVHL disease-
dc.description.journalClassY-
Appears in Collections:
Division of Research on National Challenges > 1. Journal Articles
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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