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Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1,...

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Autores principales: Rowbotham, David A., Enfield, Katey S. S., Martinez, Victor D., Thu, Kelsie L., Vucic, Emily A., Stewart, Greg L., Bennewith, Kevin L., Lam, Wan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178909/
https://www.ncbi.nlm.nih.gov/pubmed/25298778
http://dx.doi.org/10.1155/2014/546347
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author Rowbotham, David A.
Enfield, Katey S. S.
Martinez, Victor D.
Thu, Kelsie L.
Vucic, Emily A.
Stewart, Greg L.
Bennewith, Kevin L.
Lam, Wan L.
author_facet Rowbotham, David A.
Enfield, Katey S. S.
Martinez, Victor D.
Thu, Kelsie L.
Vucic, Emily A.
Stewart, Greg L.
Bennewith, Kevin L.
Lam, Wan L.
author_sort Rowbotham, David A.
collection PubMed
description Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.
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spelling pubmed-41789092014-10-08 Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma Rowbotham, David A. Enfield, Katey S. S. Martinez, Victor D. Thu, Kelsie L. Vucic, Emily A. Stewart, Greg L. Bennewith, Kevin L. Lam, Wan L. Int J Endocrinol Research Article Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation. Hindawi Publishing Corporation 2014 2014-09-14 /pmc/articles/PMC4178909/ /pubmed/25298778 http://dx.doi.org/10.1155/2014/546347 Text en Copyright © 2014 David A. Rowbotham et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Rowbotham, David A.
Enfield, Katey S. S.
Martinez, Victor D.
Thu, Kelsie L.
Vucic, Emily A.
Stewart, Greg L.
Bennewith, Kevin L.
Lam, Wan L.
Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title_full Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title_fullStr Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title_full_unstemmed Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title_short Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma
title_sort multiple components of the vhl tumor suppressor complex are frequently affected by dna copy number loss in pheochromocytoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178909/
https://www.ncbi.nlm.nih.gov/pubmed/25298778
http://dx.doi.org/10.1155/2014/546347
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