The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity

Abstract

pVHL, the product of the VHL tumor suppressor gene, plays an important role in the regulation of cell growth and differentiation of human kidney cells, and inactivation of the VHL gene is the most frequent genetic event in human kidney cancer. The biochemical function of pVHL is unknown. Here we report that pVHL exists in vivo in a complex that displays ubiquitination-promoting activity in conjunction with the universally required components E1, E2, and ubiquitin. pVHL-associated ubiquitination activity requires, at a minimum, pVHL to bind elongin C and Cul-2, relatives of core components of SCF (Skp1-Cdc53/Cul-1-F-box protein) E3 ligase complexes. Notably, certain tumor-derived mutants of pVHL demonstrate loss of associated ubiquitination promoting activity. These results identify pVHL as a component of a potential SCF-like E3 ubiquitin-protein ligase complex and suggest a direct link between pVHL tumor suppressor and the process of ubiquitination.

RKTG inhibits angiogenesis by suppressing MAPK-mediated autocrine VEGF signaling and is downregulated in clear-cell renal cell carcinoma

“…The accelerated angiogenic feature of ccRCC is best exemplified by the finding that VHL is defective in most inherited and sporadic ccRCCs. VHL is actively involved in the regulation of angiogenesis by affecting the protein stability of HIF-1a (Iwai et al, 1999;Lisztwan et al, 1999). Defective VHL, as commonly seen in ccRCC, causes an increase in HIF-1a protein level, which in turn activates transcription of VEGF and other hypoxiaresponsive genes, leading to increased angiogenesis.…”

Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development

“…pVHL has been shown to form a stable multiprotein complex which contains Elongin B (TCEB2), Elongin C (TCEB1), CUL2 and RBX1 Ohh et al, 2000). As mentioned above, this multiprotein complex has E3 ubiquitin-ligase activity, and one of its main targets is HIF1α (Lisztwan et al, 1999;Iwai et al, 1999). The importance of pVHL for proteolysis of HIF1α is further underlined by the finding that cells lacking a functional pVHL are unable to degrade this transcription factor, which ultimately results in an accumulation of HIF1α.…”

Overexpression of von Hippel-Lindau tumor suppressor protein and antisense HIF-1α eradicates gliomas

“…pVHL activates the ubiquitin-mediated degradation pathway and targets hypoxia-inducible factor-1 (HIF-1) for destruction. 5,6 Thus, functional inactivation of VHL stimulates tumor formation, in part, by increasing the stability of HIF-1. 3,7 HIF-1 regulates cellular adaptation to changes in oxygen availability by activating genes involved in angiogenesis, erythropoiesis, energy and iron metabolism, tissue matrix metabolism, and cell survival decisions, which are key factors for tumor growth and survival.…”