Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene.

Abstract

The (15)(16)(17). These factors include acidic fibroblast growth factor, basic fibroblast growth factor (bFGF), epidermal growth factor, transforming growth factors a and 13, tumor necrosis factor a, and vascular endothelial growth factor (VEGF). VEGF is secreted by a number of tumors and is normally expressed in the kidney, brain, and other tissues (18-22).VEGF is also markedly elevated in both VHL-associated and sporadic central nervous system hemangioblastomas (23, 24) and renal carcinomas (25,26). In addition to having mitogenic activity on endothelial cells, VEGF also induces vascular permeability, which may lead to extravasation of plasma proteins and deposition of fibrin, providing an extracellular support for tumor cell and endothelial cell growth.In the present study the effects of retroviral transduction of the VHL cDNA into renal carcinoma cell lines was evaluated. ITo whom reprint requests should be addressed

Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

“…One possibility could be that both HPVencoded oncoproteins, E6 and E7, impact VEGF expression and do so, not only by stimulating the activity of the promoter, but also by a ecting mRNA stability. Indeed, other oncogenes as well as the VHL tumor suppressor gene (Gnarra et al, 1996;Levy et al, 1996) have been found to increase the stability of VEGF mRNA. Additionally, other genetic changes present in the cervical cancer cells tested in the present study, may also have a positive impact on the overall level of VEGF expression.…”

The VHL tumor suppressor and HIF: insights from genetic studies in mice

“…Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers.…”

Regulation of Hypoxia-Inducible mRNAs by the von Hippel-Lindau Tumor Suppressor Protein Requires Binding to Complexes Containing Elongins B/C and Cul2

“…Loss of heterozygosity at the VHL gene locus has been described for premalignant lesions of the kidney, such as atypical cysts (32,49), suggesting that inactivation of the VHL gene is an early event in renal carcinogenesis. Furthermore, reintroduction of a wild-type but not mutant VHL cDNA into VHL (Ϫ/Ϫ) renal carcinoma cells suppresses their ability to form tumors in nude mouse xenograft assays (11,18).…”