A HIF1á REGULATORY LOOP LINKS HYPOXIA AND MITOCONDRIAL SIGNALS IN PHEOCHROMOCYTOMAS PLOS GENET.

DAHIA PLM; ROSS K,; WRIGHT ME,; HAYASHIDA CY; SANTAGATA S; BARONTINI M; KUNG AL; SANSÓ G; POWERA JA,; TISCHLER A; HODIN R,; HEITRITTER S; MOORE FJR; DLUHY R; SOSA JA; TOLGAY OCAL I; BENN DE; MARSH DJ; ROBINSON BG; SCHNEIDER K; GARBER J; ARUM SM; KORBONITS M; GROSSMAN A; PIGNY P; TOLEDO SPA; NOSÉ V; LI CH; STILES CHD

PLOS GENETICS

Año: 2005 vol. 1 p. 72 - 80

1553-7390

Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least sixindependent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here afunctional 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 inall three of these tumor types, together with an angiogenesis/hypoxiaprofile 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-offunction and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1a. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1a activity in tumors.