The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal

Arnim Pause, Stephen Lee, Kim M. Lonergan, Richard D. Klausner

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)993-998
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number3
DOIs
StatePublished - Feb 3 1998
Externally publishedYes

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Tumor Suppressor Genes
Renal Cell Carcinoma
Cell Cycle
Serum
Neoplasms
Cyclin-Dependent Kinase Inhibitor p27
Contact Inhibition
Hemangioblastoma
von Hippel-Lindau Disease
Growth
Nude Mice
Genes
Cell Culture Techniques
Kidney
Cell Line
Brain
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. / Pause, Arnim; Lee, Stephen; Lonergan, Kim M.; Klausner, Richard D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 3, 03.02.1998, p. 993-998.

Research output: Contribution to journalArticle

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