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  • The VHL tumor suppressor is a key mediator of the hypoxia response. It targets the hypoxia-inducible factor 1 subunit α (HIF1α) for ubiquitin-mediated degradation under normal oxygen conditions [[pgen-0010008-b03]]. HIF1α has been shown to be critical for the oncogenic effects resulting from VHL mutations in specific cellular contexts [[pgen-0010008-b04],[pgen-0010008-b05]]. Two other genes related to familial paraganglioma, SDHB and SDHD, encode subunits of SDH, the enzyme that composes mitochondrial complex II [[pgen-0010008-b06],[pgen-0010008-b07]]. This enzyme is both a component of the Krebs cycle, by oxidizing succinate to fumarate, and of the mitochondrial respiratory chain, by transferring electrons to the ubiquinone pool [[pgen-0010008-b08]]. Familial paragangliomas associated with SDHB and SDHD mutations resemble the carotid body growths that occur as a result of chronic hypoxia exposure in individuals living at high altitudes [[pgen-0010008-b06]]. These clinical observations and the finding of increased expression of HIF targets in tumors with SDH mutations [[pgen-0010008-b09],[pgen-0010008-b10]] have suggested the possibility that the VHL and SDH syndromes intersect at the molecular level.

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