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VHL-mediated Hypoxia Regulation of Cyclin D1 in Renal Carcinoma Cells

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development [R. S. B., R. S.]; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute [J. R. V., W. M. L.]; and Laboratory of Biosystems and Cancer, Center For Cancer Research, National Cancer Institute [R. D. K.], NIH, Bethesda, Maryland 20892

Renal cell carcinoma is associated with mutation of the von Hippel-Lindau (VHL) tumor suppressor gene. Cell lines derived from these tumors cannot exit the cell cycle when deprived of growth factors, and the ability to exit the cell cycle can be restored by the reintroduction of wild-type protein VHL (pVHL). Here, we report that cyclin D1 is overexpressed and remains inappropriately high in during contact inhibition in pVHL-deficient cell lines. In addition, hypoxia increased the expression of cyclin D1 specifically in pVHL-negative cell lines into which pVHL expression was restored. Hypoxic-induction of cyclin D1 was not observed in other pVHL-positive cell lines. This suggests a model whereby in some kidney cell types, pVHL may regulate a proliferative response to hypoxia, whereas the loss of pVHL leads to constitutively elevated cyclin D1 and abnormal proliferation under normal growth conditions.

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