2002
DOI: 10.1016/s1535-6108(02)00043-0
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Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein

Abstract: Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL(-/-) renal carcinoma cells suppresses their ability to form tumors in nude mice. Here we show that tumor suppression by pVHL can be overridden by a HIF variant that escapes pVHL control. These st… Show more

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Cited by 700 publications
(600 citation statements)
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“…8,14 CA9 as well as GLUT-1 expression is widely accepted as readout for pVHL loss and HIF stabilization. [15][16][17] To indirectly assess pVHL status, we utilized immunohistochemical staining for the HIFa target genes CA9 and GLUT1 (Table 1; Figure 1a). Strong membranous positivity of CA9 was accompanied by GLUT-1 expression in 10 of 11 ccRCCs with VHL mutation and 1 tumor was CA9 negative but showed GLUT-1 staining.…”
Section: Resultsmentioning
confidence: 99%
“…8,14 CA9 as well as GLUT-1 expression is widely accepted as readout for pVHL loss and HIF stabilization. [15][16][17] To indirectly assess pVHL status, we utilized immunohistochemical staining for the HIFa target genes CA9 and GLUT1 (Table 1; Figure 1a). Strong membranous positivity of CA9 was accompanied by GLUT-1 expression in 10 of 11 ccRCCs with VHL mutation and 1 tumor was CA9 negative but showed GLUT-1 staining.…”
Section: Resultsmentioning
confidence: 99%
“…However, recent studies have revealed that in this setting, upregulation of HIF-1a and HIF-2a activates distinct target genes and has contrasting effects on the growth of tumours (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Raval et al, 2005). These findings imply that strategies for therapeutic blockade of HIF pathways for RCC should most likely attempt to be isoform specific.…”
Section: Discussionmentioning
confidence: 99%
“…They have a highly conserved domain architecture, including sites of prolyl and asparaginyl hydroxylation, and strongly promote transcription from similar hypoxia response elements (HREs). However, there is increasing evidence for the functional non-equivalence of HIF-1a and HIF-2a, and in cancer, several recent studies have indicated that, at least in certain settings, they have contrasting effects on tumour growth (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Covello et al, 2005;Raval et al, 2005). In VHL-defective renal carcinoma cells (RCC), inactivation of HIF-a proteolysis upregulates both HIF-1a and HIF-2a with global induction of HIF target gene expression (Maxwell et al, 1999), stimulating investigations of the role of the HIF pathway in tumour development (Maranchie et al, 2002;Kondo et al, 2002Kondo et al, , 2003Zimmer et al, 2004;Raval et al, 2005).…”
mentioning
confidence: 99%
“…[42][43][44][45][46][47] At the molecular level, several HIF-2a preferentially regulated genes have been identified, including CCND1, EPO, POU5F1, TGFA, and VEGFA (encoding cyclin D1, erythropoietin, octamer-binding transcription factor 4, transforming growth factor a, vascular endothelial growth factor A, respectively). 46,48,49 However, how HIF-2a specifically targets these genes remains unclear, although the involvement of ETS transcription factors in HIF-2a target gene selection has been suggested.…”
Section: Hif-2a In Contrast With Hif-1a Promotes Cell Proliferationmentioning
confidence: 99%