RRC ID 12747
Author Baba M, Hirai S, Kawakami S, Kishida T, Sakai N, Kaneko S, Yao M, Shuin T, Kubota Y, Hosaka M, Ohno S.
Title Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth.
Journal Oncogene
Abstract In spite of the general recognition of von Hippel-Lindau (VHL) as a tumor suppressor gene, the physiological and pathological importance of VHL protein in cell growth regulation and tumorigenesis remains unclear. Here we show that in normal human renal proximal tubule epithelial cells (RPTEC), the steady-state amount of VHL protein is strictly regulated by cell density. The cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures. The increase in VHL protein at high cell density was also observed for NIH3T3 fibroblasts, suggesting the generality of the phenomenon. The growth rates of renal cell carcinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector do not differ significantly when they are growing in log-phase. Importantly, however, there is a difference when they reach confluency: cells lacking wild-type VHL grew continuously, while cells expressing exogenous VHL protein showed relatively limited cell growth. Using an ecdysone-inducible VHL expressing cell line, we also show that the growth inhibition at high cell density can be released by attenuating the VHL expression. Taken together, we propose that VHL protein functions as a growth suppressor at high cell density, and this might be the basis of the tumor suppressor function of VHL.
Volume 20(22)
Pages 2727-36
Published 2001-5-17
DOI 10.1038/sj.onc.1204397
PMID 11420685
MeSH 3T3 Cells / metabolism 3T3 Cells / pathology Animals Carcinoma, Renal Cell / metabolism Carcinoma, Renal Cell / pathology Cell Communication Cell Count* Cell Division Cell Line Genes, Tumor Suppressor* Humans Kidney Neoplasms / metabolism Kidney Neoplasms / pathology Kidney Tubules, Proximal / cytology* Kidney Tubules, Proximal / metabolism* Ligases* Mice Proteins / chemistry Proteins / genetics Proteins / metabolism* Tumor Suppressor Proteins* Ubiquitin-Protein Ligases* Von Hippel-Lindau Tumor Suppressor Protein
IF 7.971
Times Cited 38
DNA material pAxCAwt (RDB1678)