IMMUNOSTAINING OF THE VON-HIPPEL-LINDAU GENE-PRODUCT IN NORMAL AND NEOPLASTIC HUMAN TISSUES

Alterations in the von Hippel-Lindau (VHL) gene are correlated with a diverse group of neoplasms including hemangioblastoma, clear cell rena l carcinoma (RCC), and pheochromocytoma. Molecular genetic studies sug gest that VHL is a tumor-suppressor gene; corresponding ly, reintroduc tion of a VHL complementary DNA (cDNA) into RCC cells inhibits their a bility to form tumors in nude mice. Recently, it was discovered that t he VHL gene product (pVHL) binds to two subunits of the transcription elongation complex Elongin (SIII), resulting in decreased activity of this complex in vitro. It is proposed that pVHL functions in vivo as a negative regulator of transcription elongation; however, the intracel lular localization of pVHL has not been clearly delineated. Epitope-ta gged pVHL has been observed in either the nucleus or the cytoplasm of cultured cells, depending on the density of the cell culture. In this article, the cellular localization of pVHL in normal and neoplastic hu man tissues is documented using three different monoclonal antibodies. Strong expression of pVHL was observed in the epithelial cells of all organs examined, particularly in renal tubules, and was exclusively c ytoplasmic. Lesser degrees of staining, also cytoplasmic, were observe d in other cell types. A variety of carcinomas (lung, prostate, colon, breast, bladder, and thyroid) showed strong cytoplasmic staining for pVHL including four of five sporadic clear cell RCC. Of the nonepithel ial neoplasms examined, only one tumor, an embryonal rhabdomyosarcoma, failed to stain for pVHL. The findings establish widespread expressio n of VHL at the protein level and provide strong evidence that most, i f not all, pVHL is localized to the cytoplasm of cells in vivo.