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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.

VHL Induces Renal Cell Differentiation and Growth Arrest through Integration of Cell-Cell and Cell-Extracellular Matrix Signaling

Eliot J. Davidowitz,1 Alan R. Schoenfeld,1,dagger and Robert D. Burk1,2,3,*

Departments 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 1alpha , 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.

* Corresponding author. Mailing address: Ullmann Bldg. Rm. 515, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3720. Fax: (718) 430-8975. E-mail: burk{at}aecom.yu.edu.

dagger Present address: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029.

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.


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