A second major native von Hippel–Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor

Abstract

The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in both sporadic and inherited clear cell renal carcinoma associated with VHL disease. We have identified two distinct native products of the human VHL gene, with apparent molecular masses of 24 and 18 kDa. The 18-kDa VHL protein was more abundant in nearly all cell lines examined. Reintroduction of the 18-kDa VHL gene product into renal carcinoma cells lacking wild-type VHL protein led to down-regulation of vascular endothelial growth factor (VEGF) mRNA and glucose transporter GLUT1 protein and suppressed tumor formation in nude mice. The 18-kDa VHL protein also demonstrated binding to elongins B and C. In an in vitro assay, the second in-frame AUG codon present in VHL mRNA was shown to be necessary and sufficient for production of the 18-kDa VHL protein, consistent with an internal translation mechanism. These data provide evidence for a second major VHL gene product, which contains the functional domains of the VHL gene. Moreover, these results indicate that internal translation initiation is an important mechanism for production of the major VHL protein.

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

“…1) are directly driven by VHL loss, we examined chromatin changes in isogenic cell lines with and without VHL restoration. Consistent with earlier functional studies of VHL (62)(63)(64), VHL restoration in 786-O, A-498, and 12364284 cells had negligible effects on proliferation, colony formation, and apoptosis in vitro, but profoundly delayed tumor growth in vivo ( Supplementary Fig. S5A-S5D), suggesting the importance of VHL in modulating processes required for in vivo tumorigenesis, including tumor-stroma cross-talk, angiogenesis, cell-matrix interactions, or tumor metabolism.…”

Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma

“…As shown in Figure 2, Iressa plus rapamycin at various doses synergistically inhibited growth of WT8 cells. Nearly identical results were obtained using an independent stable VHL transfectant, MPR6 (Schoenfeld et al, 1998 …”

Tracheal development and the von Hippel–Lindau tumor suppressor homolog in Drosophila

“…However, no functional signi®cance has been assigned to the extra 53 amino acids at the N-terminus of the large h-VHL. Underlying this fact are the following observations: First, the short h-VHL is su cient for the tumor suppressor function (Schoenfeld et al, 1998;Blankenship et al, 1999). Second, no clinically relevant mutations have been mapped in the N-terminus (Beroud et al, 1998).…”

“…Third, the human Nterminal extension is not found in either of the two rodent (mouse and rat) VHLs. Finally, while the second initiation codon for h-VHL is¯anked by a highly conserved Kozak initiation signal, the ®rst initiation codon lacks such motif (Schoenfeld et al, 1998).…”