Abstract
Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors.
Highlights
Adrenal and extra-adrenal pheochromocytomas are catecholamine-secreting tumors derived from chromaffin cells of neural crest origin [1]
Similar to what we found in primary pheochromocytomas, no decrease in SDHB mRNA was detected when these cell lines were treated with hypoxia-mimetic drugs, suggesting that a posttranscriptional phenomenon is related to these findings
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 succinate dehydrogenase (SDH) proteins in cultured cell lines
Summary
Adrenal and extra-adrenal pheochromocytomas ( known as paragangliomas) are catecholamine-secreting tumors derived from chromaffin cells of neural crest origin [1]. The VHL tumor suppressor is a key mediator of the hypoxia response It targets the hypoxia-inducible factor 1 subunit a (HIF1a) for ubiquitin-mediated degradation under normal oxygen conditions [3]. Two other genes related to familial paraganglioma, SDHB and SDHD, encode subunits of SDH, the enzyme that composes mitochondrial complex II [6,7]. This enzyme is both a component of the Krebs cycle, by oxidizing succinate to fumarate, and of the mitochondrial
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
