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

Sutapa Sinha, Gourish Mondal, Eun Ju Hwang, Da Woon Han, Shamit K. Dutta, Seethalakshmi Iyer, S. Ananth Karumanchi, Keun Il Kim, Fergus J. Couch, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2132-2142
Number of pages11
JournalJournal of cell science
Volume124
Issue number13
DOIs
StatePublished - Jul 1 2011

Keywords

  • Alix
  • Cin
  • Cytokinesis
  • Endobrevin
  • Pvhl
  • SUMOylation

ASJC Scopus subject areas

  • Cell Biology

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    Sinha, S., Mondal, G., Hwang, E. J., Han, D. W., Dutta, S. K., Iyer, S., Karumanchi, S. A., Kim, K. I., Couch, F. J., & Mukhopadhyay, D. (2011). Von Hippel-Lindau gene product directs cytokinesis: A new tumor suppressor function. Journal of cell science, 124(13), 2132-2142. https://doi.org/10.1242/jcs.087122