A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.
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...
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2005-07-01
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doaj-7bb7eecfd11145148cad35a3854632b42020-11-25T01:32:48ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042005-07-0111728010.1371/journal.pgen.0010008A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.Patricia L M DahiaKen N RossMatthew E WrightCésar Y HayashidaSandro SantagataMarta BarontiniAndrew L KungGabriela SansoJames F PowersArthur S TischlerRichard HodinShannon HeitritterFrancis MooreRobert DluhyJulie Ann SosaI Tolgay OcalDiana E BennDeborah J MarshBruce G RobinsonKatherine SchneiderJudy GarberSeth M ArumMárta KorbonitsAshley GrossmanPascal PignySérgio P A ToledoVania NoséCheng LiCharles D StilesPheochromocytomas 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 HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.http://europepmc.org/articles/PMC1183527?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patricia L M Dahia Ken N Ross Matthew E Wright César Y Hayashida Sandro Santagata Marta Barontini Andrew L Kung Gabriela Sanso James F Powers Arthur S Tischler Richard Hodin Shannon Heitritter Francis Moore Robert Dluhy Julie Ann Sosa I Tolgay Ocal Diana E Benn Deborah J Marsh Bruce G Robinson Katherine Schneider Judy Garber Seth M Arum Márta Korbonits Ashley Grossman Pascal Pigny Sérgio P A Toledo Vania Nosé Cheng Li Charles D Stiles |
spellingShingle |
Patricia L M Dahia Ken N Ross Matthew E Wright César Y Hayashida Sandro Santagata Marta Barontini Andrew L Kung Gabriela Sanso James F Powers Arthur S Tischler Richard Hodin Shannon Heitritter Francis Moore Robert Dluhy Julie Ann Sosa I Tolgay Ocal Diana E Benn Deborah J Marsh Bruce G Robinson Katherine Schneider Judy Garber Seth M Arum Márta Korbonits Ashley Grossman Pascal Pigny Sérgio P A Toledo Vania Nosé Cheng Li Charles D Stiles A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genetics |
author_facet |
Patricia L M Dahia Ken N Ross Matthew E Wright César Y Hayashida Sandro Santagata Marta Barontini Andrew L Kung Gabriela Sanso James F Powers Arthur S Tischler Richard Hodin Shannon Heitritter Francis Moore Robert Dluhy Julie Ann Sosa I Tolgay Ocal Diana E Benn Deborah J Marsh Bruce G Robinson Katherine Schneider Judy Garber Seth M Arum Márta Korbonits Ashley Grossman Pascal Pigny Sérgio P A Toledo Vania Nosé Cheng Li Charles D Stiles |
author_sort |
Patricia L M Dahia |
title |
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
title_short |
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
title_full |
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
title_fullStr |
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
title_full_unstemmed |
A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
title_sort |
hif1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2005-07-01 |
description |
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 HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors. |
url |
http://europepmc.org/articles/PMC1183527?pdf=render |
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