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

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.

[1]  D. Mukhopadhyay,et al.  Von Hippel-Lindau Gene Product Modulates TIS11B Expression in Renal Cell Carcinoma , 2009, The Journal of Biological Chemistry.

[2]  D. Mukhopadhyay,et al.  Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2 , 2009, Journal of Cell Science.

[3]  H. Moch,et al.  VHL loss causes spindle misorientation and chromosome instability , 2009, Nature Cell Biology.

[4]  V. Pankratz,et al.  Microcephalin regulates BRCA2 and Rad51-associated DNA double-strand break repair. , 2009, Cancer research.

[5]  D. Mukhopadhyay,et al.  VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma , 2008, Journal of cellular and molecular medicine.

[6]  C. Croce,et al.  MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis , 2008, Proceedings of the National Academy of Sciences.

[7]  S. Gygi,et al.  Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis , 2007, The EMBO journal.

[8]  R. Green,et al.  APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice , 2007, The Journal of cell biology.

[9]  L. Truong,et al.  Expression of GLUT1 in primary renal tumors: morphologic and biologic implications. , 2007, American journal of clinical pathology.

[10]  J. Martin-Serrano,et al.  Parallels Between Cytokinesis and Retroviral Budding: A Role for the ESCRT Machinery , 2007, Science.

[11]  Kentaro Takahashi,et al.  [Von Hippel-Lindau disease]. , 2006, Nihon rinsho. Japanese journal of clinical medicine.

[12]  E. Cho,et al.  p53 stabilization and transactivation by a von Hippel-Lindau protein. , 2006, Molecular cell.

[13]  A. Terzic,et al.  Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice , 2006, The Journal of cell biology.

[14]  David Pellman,et al.  Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells , 2005, Nature.

[15]  K. Khanna,et al.  Cdk1/Erk2- and Plk1-dependent phosphorylation of a centrosome protein, Cep55, is required for its recruitment to midbody and cytokinesis. , 2005, Developmental cell.

[16]  W. Kaelin,et al.  Role of VHL gene mutation in human cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  E. Voest,et al.  The von Hippel-Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery. , 2004, Experimental cell research.

[18]  A. Venkitaraman,et al.  Abnormal Cytokinesis in Cells Deficient in the Breast Cancer Susceptibility Protein BRCA2 , 2004, Science.

[19]  M. Guo,et al.  Expression of fibronectin and HIF-1alpha in renal cell carcinomas: relationship to von Hippel-Lindau gene inactivation. , 2004, Cancer genetics and cytogenetics.

[20]  Hongmei Wang,et al.  Tumor Suppressor von Hippel-Lindau (VHL) Stabilization of Jade-1 Protein Occurs through Plant Homeodomains and Is VHL Mutation Dependent , 2004, Cancer Research.

[21]  W. Sundquist,et al.  The Protein Network of HIV Budding , 2003, Cell.

[22]  A. Calistri,et al.  AIP1/ALIX Is a Binding Partner for HIV-1 p6 and EIAV p9 Functioning in Virus Budding , 2003, Cell.

[23]  T. Weimbs,et al.  Syntaxin 2 and endobrevin are required for the terminal step of cytokinesis in mammalian cells. , 2003, Developmental cell.

[24]  I. Kuzmin,et al.  The von Hippel-Lindau Tumor Suppressor Stabilizes Novel Plant Homeodomain Protein Jade-1* , 2002, The Journal of Biological Chemistry.

[25]  Min Wang,et al.  The Small Ubiquitin-like Modifier-1 (SUMO-1) Consensus Sequence Mediates Ubc9 Binding and Is Essential for SUMO-1 Modification* , 2001, The Journal of Biological Chemistry.

[26]  R. Hay,et al.  SUMO-1 Conjugation in Vivo Requires Both a Consensus Modification Motif and Nuclear Targeting* , 2001, The Journal of Biological Chemistry.

[27]  S. Sen,et al.  Aneuploidy and cancer , 2000, Current opinion in oncology.

[28]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[29]  W. Kaelin,et al.  Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. , 1999, Science.

[30]  R. Burk,et al.  A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Louis,et al.  The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. , 1998, Molecular cell.

[32]  M. Goldberg,et al.  Hypoxia-inducible Protein Binding to Vascular Endothelial Growth Factor mRNA and Its Modulation by the von Hippel-Lindau Protein* , 1996, The Journal of Biological Chemistry.

[33]  R. Klausner,et al.  Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[34]  W. Kaelin,et al.  Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Martiny-Baron,et al.  Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. , 1996, Cancer research.

[36]  A. Kibel,et al.  Tumour suppression by the human von Hippel-Lindau gene product , 1995, Nature Medicine.

[37]  M. Lerman,et al.  Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. , 1994, Human molecular genetics.

[38]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[39]  M. Lerman,et al.  Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. , 1994, Human molecular genetics.

[40]  W. Linehan,et al.  Mapping the Von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis. , 1993, Human molecular genetics.

[41]  E. Voest,et al.  Tumor suppressors APC and VHL: gatekeepers of the intestine and kidney. , 2005, Progress in molecular and subcellular biology.

[42]  F. Speleman,et al.  Rapid detection of VHL exon deletions using real-time quantitative PCR , 2005, Laboratory Investigation.

[43]  W. Krek,et al.  Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL , 2003, Nature Cell Biology.

[44]  W. Linehan,et al.  Improved detection of germline mutations in the von Hippel‐Lindau disease tumor suppressor gene , 1998, Human mutation.

[45]  W. Linehan,et al.  Germline mutations in the Von Hippel‐Lindau disease (VHL) gene in families from North America, Europe, and Japan , 1996, Human mutation.

[46]  in the protein , 2022 .