Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.

By K. Kondo, Jeffery M Klco, E. Nakamura, Mirna Lechpammer, W. Kaelin. Cancer Cell, 2002

810 citations recorded by the source corpus.

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 studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/73765cce50976a60fa01ba1a8cf526ce4e03a11b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. G. Semenza
2. C. V. Dang
3. M. C. Simon
4. W. Kaelin
5. J. Pouysségur
6. P. Ratcliffe
7. Jung-whan Kim
8. P. Schumacker

In Molecular Biology

1. G. Semenza
2. C. V. Dang
3. M. C. Simon
4. W. Kaelin
5. J. Pouysségur
6. P. Ratcliffe
7. Jung-whan Kim
8. Ping Gao

Citations in the corpus

• The genetic basis of kidney cancer: a metabolic disease (2010, background): “Although considerable overlap exists in the genes that are transcriptionally regulated by HIF1-α and HIF2-α, in vitro and in vivo studies have indicated that HIF2-α is the critical HIF for tumorigenesis in clear cell kidney cancer”
• Molecular basis of the VHL hereditary cancer syndrome (2002, background): “The importance of HIF with respect to renal carcinogenesis is highlighted by two recent studies showing that HIF-α variants that were engineered to escape recognition by pVHL could override pVHL's tumour-suppressor activities in vitro and in vivo”
• HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. (2007, background): “HIF-1 is required for tumorigenesis in VHL-deficient renal carcinoma cells (Kondo et al., 2002; Maranchie et al., 2002).”
• Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation (2003, positive): “This unique function of HIF-1 in regulating the glycolytic pathway may partially explain why HIF-2 , and not HIF-1 , promotes tumorigenesis in 786-O renal clear cell carcinoma (53, 64).”
• Hypoxia signalling in cancer and approaches to enforce tumour regression (2006, background): “Perhaps the best example concerns the renal cell carcinoma line 786-0, lacking VHL, in which it was elegantly demonstrated that HIF-2α expression was indeed causal for tumour growt”
• HIF‐1α induces cell cycle arrest by functionally counteracting Myc (2004, background): “Undoubtedly, further investigation is warranted for a better understanding of the divergent roles of HIF-1a and HIF-2a in tumorigenesis.”
• The role of hypoxia-inducible factors in tumorigenesis (2008, background): “In VHL-deficient RCC cells, HIF-2 is both necessary and sufficient to maintain tumor growth.(71,72) Furthermore, tumors generated from RCC cell lines overexpressing HIF-2 grow at a faster rate compared to HIF-1-overexpressing tumors.”
• Cancer genes and the pathways they control (2004, background): “Third, inactivation of VHL , a classic tumor-suppressor gene, was shown to support renal cell tumor growth through the control of tumor angiogenesi”
• The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer (2008, background): “Second, overproduction of HIF2α (for example, using a stabilized version of HIF2α lacking its prolyl hydroxylation sites), but not HIF1α, is sufficient to override the tumour suppressor function of VHL in xenograft studie”
• HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. (2007, background): “O RCC cells expressing pVHL restores xenograft growth to the level of parental VHL null cells (Kondo et al., 2002, 2003; Raval et al., 2005), whereas overexpression of stable HIF-1a inhibits tumor growth (Maranchie et al., 2002; Raval et al., 2005).”
• Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1 (2007, background): “However, there is emerging evidence that HIF-2 may play more prominent roles in tumorigenesis (10, 11, 39, 41, 51, 79).”