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Transforming Growth Factor Is a Target for the Von Hippel-Lindau Tumor Suppressor¹

Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The von Hippel-Lindau (VHL) tumor suppressor gene has a critical role in the pathogenesis of clear cell renal cell carcinoma (RCC), because VHL mutations have been found in both VHL disease-associated and sporadic RCC. Overexpression of transforming growth factor (TGF)- has been observed in numerous RCC tumors and cell lines, and TGF- has been demonstrated to support RCC cell growth through an autocrine loop. We demonstrate here that VHL substantially decreases TGF- message and protein by shortening TGF- mRNA half-life. By Northern analysis TGF- mRNA steady-state levels were suppressed 5-fold in permanent 786-0 RCC cell lines expressing wild-type VHL compared with 786-0 cells expressing an empty vector or a mutant VHL protein lacking COOH-terminal residues 116–213 (VHL). By Western analysis, VHL also substantially down-regulated the unprocessed, cell-associated M_r 20,000 TGF- protein. Moreover, secreted TGF- was undetectable in VHL-expressing cells. In contrast, VHL did not down-regulate the TGF- receptor, epidermal growth factor receptor, either at the mRNA or protein level. Nuclear run-on in vitro transcription experiments in 786-0 cells showed that VHL did not affect transcriptional control of the endogenous TGF- gene. However, actinomycin D experiments revealed a long TGF- mRNA half-life in 786-0 cells that was significantly decreased by wild-type VHL but not by VHL. We have, therefore, identified TGF-, an important growth factor for RCC, as a new target gene for VHL and demonstrated that VHL acts by decreasing TGF- mRNA stability.

¹ This work was partly supported by an NIH National Institutes of Diabetes, Digestive and Kidney Diseases grant (to V. P. S.), a grant from the Foundation pour la Recherche Medicale (to B. K.), and NIH Grant DK02280 (to H. T. C.).

² To whom requests for reprints should be addressed, at Department of Medicine, Beth Israel Deaconess Medical Center. Harvard Medical School, 330 Brookline Avenue, Dana 517, Boston, MA 02215. Phone: (617) 667-2105; Fax: (617) 667-7843; E-mail: vsukhatm@bidmc.harvard.edu.

Received 10/ 3/97. Accepted 11/19/97.

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