The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal.
The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes affected individuals to the human VHL cancer syndrome and is associated with sporadic renal cell carcinomas (RCC) and brain hemangioblastomas. VHL-negative 786-0 RCC cells are tumorigenic in nude mice which is suppressed by the reintroduction of VHL. Remarkably, this occurs without affecting the growth rate and cell cycle profile of these cells in culture. The 786-0 cell line, like many cancer cells, fails to exit the cell cycle upon serum withdrawal. Here, it is shown that reintroduction of the wild-type VHL gene restores the ability of VHL-negative RCC cancer cells to exit the cell cycle and enter G0/quiescence in low serum. Both VHL-positive and VHL-negative RCC cells exit the cell cycle by contact inhibition. The cyclin-dependent kinase inhibitor, p27, accumulates upon serum withdrawal, only in the presence of VHL, as a result of the stabilization of the protein. We propose that the loss of wild-type VHL gene results in a specific cellular defect in serum-dependent growth control, which may initiate tumor formation. This is corrected by the reintroduction of wild-type VHL, implicating VHL as the first tumor suppressor involved in the regulation of cell cycle exit, which is consistent with its gatekeeper function in the kidney.
Pause
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Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. apause@box-a.nih.gov
Lee
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S
Lonergan
K M
KM
Klausner
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RD
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D003260:Contact Inhibition; D016895:Culture Media, Serum-Free; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008025:Ligases; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D018844:Cyclin-Dependent Kinases; D008025:Ligases; C497446:VHL protein, human