Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

Ang, Sonny; Chen, Hua; Hirota, Kiichi; Gordeuk, Victor R.; Jelı́nek, Jaroslav; Guan, Yongli; Liu, Enli; Sergueeva, Adelina; Miasnikova, Galina Y.; Mole, David R.; Maxwell, Patrick H.; Stockton, David W.; Semenza, Gregg L.; Prchal, Josef T.

doi:10.1038/ng1019

Cited by 452 publications

(421 citation statements)

References 30 publications

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“…Distinct VHL mutations that prevent the binding of HIF-␣s, and thus their subsequent pVHL-mediated degradation, can lead to HIF-dependent Epo production and a hereditary polycythemia known as Chuvash polycythemia (36), or a cancer syndrome (2,37) that is characterized by highly vascular tumors that overproduce hypoxia-inducible mRNAs such as those for VEGF. SDH and FH mutations likewise predispose to dominantly inherited highly vascular tumors, findings in SDH mutations including pheochromocytoma, paraganglioma, renal cell carcinoma, and papillary thyroid cancer (18, 38 -40) and those in FH mutations oncluding uterine fibroids, skin leiomyomata, and papillary renal cell cancer (19,38,41).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

Koivunen

Hirsilä

Remes

et al. 2007

Journal of Biological Chemistry

457

375

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Section: Discussionmentioning

confidence: 99%

Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

Koivunen

Hirsilä

Remes

et al. 2007

Journal of Biological Chemistry

457

375

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“…This may be due to a degree of redundancy in the activity of different PHDs. Interestingly, recent studies have identified specific familial mutations in PHD2 and pVHL, each of which leads to erythrocytosis associated with HIF induction, but none of which is associated with cancer (Ang et al, 2002;Percy, 2006). 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.…”

Section: Open Questions and Future Directionsmentioning

confidence: 99%

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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“…This mutation is transmitted in an autosomal-recessive manner, and affected individuals, who are homozygous for the mutation, are not predisposed to the development of typical VHL-associated tumors. 75 In mice, germ-line loss of one VHL allele (VHL þ /À) results in the development of cavernous liver hemangiomas, 76 which is a rare manifestation of VHL disease in human. 77,78 This phenotype is strongly dependent on the genetic background of heterozygous mice, as the incidence of liver hemangiomas in BALB/c mice was 88%, but only 18% in a C57BL/6 background, most likely reflecting polymorphic differences in modifier genes.…”

Section: Vhl Disease Manifestations In Mice With Germ-line Mutationsmentioning

confidence: 99%

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

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. 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. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

Cited by 452 publications

References 30 publications

Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

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

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