Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α

Elson, David A.; Thurston, Gavin; Huang, L. Eric; Ginzinger, David G.; McDonald, Donald M.; Johnson, Randall S.; Arbeit, Jeffrey M.

doi:10.1101/gad.914801

Cited by 280 publications

(236 citation statements)

References 53 publications

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“…Perhaps, cancer in these cases is avoided because HIF induction is relatively low (this was not yet evaluated) or because pseudo-hypoxia alone is insufficient to induce tumorigenesis. The latter hypothesis is supported by the observation that mice transgenic for a non-degradable cutaneous HIF1a mutant were not reported to develop tumours (Elson et al, 2001).…”

Section: Open Questions and Future Directionsmentioning

confidence: 84%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Section: Open Questions and Future Directionsmentioning

confidence: 84%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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“…These skin phenotypes are similar to those observed in HIF-1a-overexpressing mice described previously. 30 …”

Section: Activation Of Hif and Induction Of Hif-regulated Genes By Comentioning

confidence: 99%

Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model

Tanaka

Kojima

Ohse

et al. 2005

Laboratory Investigation

220

141

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Tubulointerstitial hypoxia has been implicated in a number of progressive renal diseases, and several lines of evidence indicate that the administration of angiogenic growth factors ameliorates tubulointerstitial injury. We hypothesized that induction of hypoxia-inducible factors (HIF) mediates renoprotection by their angiogenic properties. At 5-9 weeks after subtotal nephrectomy, cobalt was administered to rats to activate HIF. Histological evaluation demonstrated that the tubulointerstitial injury was significantly ameliorated in animals that received cobalt (score: 2.5170.12 (cobalt) vs 3.2170.24 (vehicle), Po0.05). Furthermore, animals receiving cobalt had fewer vimentin-and TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. The renoprotective effect of cobalt was associated with the preservation of peritubular capillary networks (rarefaction index: 13.770.4 (cobalt) vs 18.670.9 (vehicle), Po0.01). This improvement in capillary networks was accompanied by an increased number of proliferating (PCNA-positive) glomerular and peritubular endothelial cells. The angiogenesis produced by this method was not accompanied by an increase in vascular permeability. Furthermore, in vitro experiments clarified that HIF-1 in tubular epithelial cells promotes proliferation of endothelial cells and that HIF-2 overexpressed in renal endothelial cells mediates migration and network formation. Collectively, these findings demonstrate a renoprotective role of HIF through angiogenesis and provide a rationale for therapeutic approaches to target HIF for activation.

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“…It is interesting that these families do not seem to be at markedly increased risk for tumor formation. Perhaps in keeping with this observation, forced activation of HIF target genes in animal models has not given rise to tumors in the tissues examined to date (92)(93)(94). Collectively, these considerations point to pVHL's having multiple functions, with site-specific tumor risk determined by the degrees to which these various functions are quantitatively or qualitatively altered.…”

Section: Pvhl-hypoxia-inducible Factor Connectionmentioning

confidence: 74%

The von Hippel-Lindau Gene, Kidney Cancer, and Oxygen Sensing

Kaelin¹

2003

Journal of the American Society of Nephrology

119

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Abstract. Recent studies of a relatively rare hereditary cancer syndrome, von Hippel-Lindau (VHL) disease, have shed new light on the molecular pathogenesis of kidney cancer and, perhaps more important, on how mammalian cells sense and respond to changes in oxygen availability. This knowledge is already translating into new therapeutic targets for kidney cancer as well as for multiple conditions, such as myocardial infarction and stroke, in which ischemia plays a pathogenic role. This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway.

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Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α

Cited by 280 publications

References 53 publications

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model

The von Hippel-Lindau Gene, Kidney Cancer, and Oxygen Sensing

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