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- Title
A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas.
- Authors
Dahia, Patricia L. M.; Ross, Ken N.; Wright, Matthew E.; Hayashida, César Y.; Santagata, Sandro; Barontini, Marta; Kung, Andrew L.; Sanso, Gabriela; Powers, James F.; Tischler, Arthur S.; Hodin, Richard; Heitritter, Shannon; Moore Jr., Francis; Dluhy, Robert; Sosa, Julie Ann; Ocal, I. Tolgay; Benn, Diana E.; Marsh, Deborah J.; Robinson, Bruce G.; Schneider, Katherine
- 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.
- Subjects
PHEOCHROMOCYTOMA; GENETIC mutation; TUMORS; GENETIC code; MITOCHONDRIA; NEURAL crest; EMBRYOLOGY
- Publication
PLoS Genetics, 2005, Vol 1, Issue 1, p72
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.0010008