A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas

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 Nose; Cheng Li; Charles D. Stiles

doi:10.1371/journal.pgen.0010008

A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas

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 SchneiderJudy Garber, Seth M. Arum, Márta Korbonits, Ashley Grossman, Pascal Pigny, Sérgio P.A. Toledo, Vania Nose, Cheng Li, Charles D. Stiles

Research output: Contribution to journal › Article › peer-review

372 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	72-80
Number of pages	9
Journal	PLoS Genetics
Volume	1
Issue number	1
DOIs	https://doi.org/10.1371/journal.pgen.0010008
State	Published - Jul 2005
Externally published	Yes

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Dahia, P. L. M., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M., Kung, A. L., Sanso, G., Powers, J. F., Tischler, A. S., Hodin, R., Heitritter, S., Moore, F., Dluhy, R., Sosa, J. A., Ocal, I. T., Benn, D. E., Marsh, D. J., Robinson, B. G., ... Stiles, C. D. (2005). A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genetics, 1(1), 72-80. https://doi.org/10.1371/journal.pgen.0010008

Dahia, PLM, Ross, KN, Wright, ME, Hayashida, CY, Santagata, S, Barontini, M, Kung, AL, Sanso, G, Powers, JF, Tischler, AS, Hodin, R, Heitritter, S, Moore, F, Dluhy, R, Sosa, JA, Ocal, IT, Benn, DE, Marsh, DJ, Robinson, BG, Schneider, K, Garber, J, Arum, SM, Korbonits, M, Grossman, A, Pigny, P, Toledo, SPA, Nose, V, Li, C & Stiles, CD 2005, 'A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas', PLoS Genetics, vol. 1, no. 1, pp. 72-80. https://doi.org/10.1371/journal.pgen.0010008

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title = "A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas",

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 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.",

author = "Dahia, {Patricia L.M.} and Ross, {Ken N.} and Wright, {Matthew E.} and Hayashida, {C{\'e}sar Y.} and Sandro Santagata and Marta Barontini and Kung, {Andrew L.} and Gabriela Sanso and Powers, {James F.} and Tischler, {Arthur S.} and Richard Hodin and Shannon Heitritter and Francis Moore and Robert Dluhy and Sosa, {Julie Ann} and Ocal, {I. Tolgay} and Benn, {Diana E.} and Marsh, {Deborah J.} and Robinson, {Bruce G.} and Katherine Schneider and Judy Garber and Arum, {Seth M.} and M{\'a}rta Korbonits and Ashley Grossman and Pascal Pigny and Toledo, {S{\'e}rgio P.A.} and Vania Nose and Cheng Li and Stiles, {Charles D.}",

year = "2005",

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doi = "10.1371/journal.pgen.0010008",

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AU - Dahia, Patricia L.M.

AU - Ross, Ken N.

AU - Wright, Matthew E.

AU - Hayashida, César Y.

AU - Santagata, Sandro

AU - Barontini, Marta

AU - Kung, Andrew L.

AU - Sanso, Gabriela

AU - Powers, James F.

AU - Tischler, Arthur S.

AU - Hodin, Richard

AU - Heitritter, Shannon

AU - Moore, Francis

AU - Dluhy, Robert

AU - Sosa, Julie Ann

AU - Ocal, I. Tolgay

AU - Benn, Diana E.

AU - Marsh, Deborah J.

AU - Robinson, Bruce G.

AU - Schneider, Katherine

AU - Garber, Judy

AU - Arum, Seth M.

AU - Korbonits, Márta

AU - Grossman, Ashley

AU - Pigny, Pascal

AU - Toledo, Sérgio P.A.

AU - Nose, Vania

AU - Li, Cheng

AU - Stiles, Charles D.

PY - 2005/7

Y1 - 2005/7

N2 - 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 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.

AB - 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 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.

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A HIf1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas

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