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Laboratory of Immunobiology, National Cancer Institute [T. K., M. I. L., B. Z.], and Biological Carcinogenesis and Development Program, Science Applications International Corporation [T. S., F. C.], National Cancer Institute-Frederick Cancer Research Facility and Development Center, Frederick, Maryland 21702-1201
The von Hippel-Lindau disease (VHL) gene is a novel tumor suppressor gene that plays a role in the pathogenesis of renal cell carcinomas and hemangioblastomas of the central nervous system. To begin an evaluation of the biological functions of the VHL gene product (pVHL), we prepared bacterial fusion protein between glutathione S-transferase and wild-type or mutant pVHLs. The fusion proteins were used to identify cellular proteins that bind to pVHL in vitro. Monkey kidney cells transfected with wild-type or mutant VHL cDNAs were used to identify cellular proteins that bind to pVHL in vivo. Wild-type pVHL consistently bound two cellular proteins with apparent molecular masses of 10 and 14 kilodaltons that were designated p10 and p14, respectively. Mapping studies with a panel of VHL deletion mutant proteins demonstrated that p10 and p14 bound to a 32-amino acid peptide located in the carboxy terminal portion of pVHL. Missense mutations located within this 32-amino acid peptide abrogated the ability of the VHL protein to bind p10 and p14. Of 67 VHL families with identified germline mutations, 42 families had mutations predicted to affect the p10/p14-binding region. Maintenance of the integrity of the p10/p14-binding region appears to be essential for cellular growth regulation by pVHL.
1 To whom requests for reprints should be addressed, at Laboratory of Immunobiology, Building 560, Room 12-71, National Cancer Institute-Frederick Cancer Research Facility and Development Center, Frederick, MD 21702-1201.
Received 7/26/95. Accepted 8/28/95.
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