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  • Transcription profiling of a large series of primary pheochromocytomas reveals that tumors with VHL and SDH mutations are closely linked. The hypoxia-angiogenesis signature identified by our analysis of primary tumors with SDHB or SDHD mutations confirms and extends recent observations on the role of SDH proteins in cultured cell lines. Selak et al. showed that disruption of the mitochondrial complex II results in increased HIF1α activity and that this upregulation is channeled through inhibition of prolyl hydroxylase function [[pgen-0010008-b19]]. This hydroxylation step is essential for VHL-dependent HIF1α degradation [[pgen-0010008-b20],[pgen-0010008-b21]]. Our data show that mitochondrial complex II mutations lead to upregulation of HIF1α targets in human tumor tissue and indicate an additional level of interplay between the SDHB and HIF1α proteins, i.e., a reciprocal effect of HIF1α in modulating components of the mitochondrial complex II. Our findings favor the existence of an autoregulatory loop whereby HIF1α contributes to attenuation of SDHB levels, resulting in complex II inhibition ([pgen-0010008-g004]D). High levels of succinate resulting from loss of complex II function can in turn block HIF1α degradation through inhibition of prolyl hydroxylases. However, while succinate accumulation, but not oxidative stress, was considered the oncogenic trigger by Selak et al. [[pgen-0010008-b19]], increased levels of reactive oxygen species have been reported in animal models of SDHC dysfunction [[pgen-0010008-b22]–[pgen-0010008-b24]]. The latter results are consistent with the oxidoreductase defect of our primary tumor samples. The precise mechanisms for the interaction between HIF1α and SDHB still remain to be identified, but our data suggest that a posttranscriptional response is likely to be involved. Of note, and in keeping with our current data, HIF2α /EPAS1-null mice were reported to have increased SDH activity in muscle [[pgen-0010008-b25]].


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