Molecular and Cellular Biology, February 2001, p. 865-874, Vol. 21, No. 3
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.3.865-874.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
andDepartments of Microbiology and Immunology,1 Pediatrics,2 and Epidemiology and Social Medicine,3 Marion Bessin Liver Research Center and Albert Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461
Received 20 September 2000/Returned for modification 24 October 2000/Accepted 7 November 2000
Mutations in the von Hippel-Lindau (VHL) gene are involved in the
family cancer syndrome for which it is named and the development of
sporadic renal cell cancer (RCC). Reintroduction of VHL into RCC cells
lacking functional VHL [VHL(
)] can suppress their growth in nude
mice, but not under standard tissue culture conditions. To
examine the hypothesis that the tumor suppressor function of VHL
requires signaling through contact with extracellular matrix (ECM), 786-O VHL(
) RCC cells and isogenic sublines stably expressing VHL gene products [VHL(+)] were grown on ECMs. Cell-cell and cell-ECM signalings were required to elicit VHL-dependent
differences in growth and differentiation. VHL(+) cells differentiated
into organized epithelial sheets, whereas VHL(
) cells
were branched and disorganized. VHL(+) cells grown to high density on
collagen I underwent growth arrest, whereas VHL(
)
cells continued to proliferate. Integrin levels were up-regulated in
VHL(
) cells, and cell adhesion was down-regulated in VHL(+)
cells during growth at high cell density. Hepatocyte nuclear factor
1
, a transcription factor and global activator of proximal
tubule-specific genes in the nephron, was markedly up-regulated in
VHL(+) cells grown at high cell density. These data indicate that
VHL can induce renal cell differentiation and mediate
growth arrest through integration of cell-cell and cell-ECM signals.
Present address: Derald H. Ruttenberg Cancer Center, Mount Sinai
School of Medicine, New York, NY 10029.
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