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

Cited 10 time in scopus
Metadata Downloads
Title
E2-EPF UCP regulates stability and functions of missense mutant pVHL via ubiquitin mediated proteolysis
Author(s)
Kyeong Su Park; Ju Hee Kim; Hee Won Shin; Kyung-Sook Chung; Dong-Soo Im; Jung Hwa LimCho Rok Jung
Bibliographic Citation
BMC Cancer, vol. 15, pp. 800-800
Publication Year
2015
Abstract
Background: 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.
Keyword
E2-EPF UCPProtein instabilitypVHL missense mutationUbiquitinationVHL disease
ISSN
1471-2407
Publisher
Springer-BMC
DOI
http://dx.doi.org/10.1186/s12885-015-1786-8
Type
Article
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
Files in This Item:

Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.