title: Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Foundation, Rochester, MN 55905, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Sinha
authors.forename: Gourish
authors.initials: G
authors.lastname: Mondal
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Hwang
authors.forename: Da Woon
authors.initials: da W
authors.lastname: Han
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.forename: Seethalakshmi
authors.initials: S
authors.lastname: Iyer
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D048749:Cytokinesis / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011123:Polyploidy; D050683:R-SNARE Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C492144:Pdcd6ip protein, mouse; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C491831:Vamp8 protein, mouse; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse