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Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function

Authors
Sinha, SutapaMondal, GourishHwang, Eun JuHan, Da WoonDutta, Shamit K.Iyer, SeethalakshmiKarumanchi, S. AnanthKim, Keun IlCouch, Fergus J.Mukhopadhyay, Debabrata
Issue Date
Jul-2011
Publisher
COMPANY BIOLOGISTS LTD
Keywords
pVHL; CIN; SUMOylation; Cytokinesis; Alix; Endobrevin
Citation
JOURNAL OF CELL SCIENCE, v.124, no.13, pp 2132 - 2142
Pages
11
Journal Title
JOURNAL OF CELL SCIENCE
Volume
124
Number
13
Start Page
2132
End Page
2142
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/12538
DOI
10.1242/jcs.087122
ISSN
0021-9533
1477-9137
Abstract
One of the mechanisms of tumorigenesis is that the failure of cell division results in genetically unstable, multinucleated cells. Here we show that pVHL, a tumor suppressor protein that has been implicated in the pathogenesis of renal cell carcinoma (RCC), plays an important role in regulation of cytokinesis. We found that pVHL-deficient RCC 786-O cells were multinucleated and polyploid. Reintroduction of wild-type pVHL into these cells rescued the diploid cell population, whereas the mutant pVHL-K171G failed to do so. We demonstrate that lysine 171 of pVHL is important for the final step of cytokinesis: the midbody abscission. The pVHL-K171G caused failure to localize the ESCRT-1 interacting protein Alix and the v-SNARE complex component Endobrevin to the midbody in 786-O cells, leading to defective cytokinesis. Moreover, SUMOylation of pVHL at lysine 171 might modulate its function as a cytokinesis regulator. pVHL tumor suppressor function was also disrupted by the K171G mutation, as evidenced by the xenograft tumor formation when 786-O clones expressing pVHL-K171G were injected into mice. Most RCC cell lines show a polyploid chromosome complement and consistent heterogeneity in chromosome number. Thus, this study offers a way to explain the chromosome instability in RCC and reveals a new direction for the tumor suppressor function of pVHL, which is independent of its E3 ubiquitin ligase activity.
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