TY - GEN
T1 - Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas
AU - Dahia, Patricia L.M.
PY - 2006/8
Y1 - 2006/8
N2 - Pheochromocytomas and paragangliomas are neural-crest-derived tumors that arise from mutations in RET, VHL, NF1, and in the genes-encoding succinate dehydrogenase (SDH) subunits B (SDHB), C (SDHC), and D (SDHD). Despite their genetic diversity, these tumors cannot be clearly distinguished on the basis of their primary mutation. We recently identified two major transcriptional programs embedded within familial and sporadic pheochromocytomas and paragangliomas using global expression profiling. This review will summarize the major results of these studies and discuss their implications. The transcription data revealed that: (a) tumors with mutations in VHL, SDHB, and SDHD genes share a transcription signature of hypoxia, angiogenesis, and oxidoreductase imbalance; (b) SDHB protein is suppressed in tumors with mutations in SDHB and SDHD, and also in a subset of tumors with VHL mutations; and (c) HIF1α is involved in the SDHB downregulation observed in these tumors. These results are consistent with the existence of a close interconnection between the VHL and SDH pathways mediated predominantly by hypoxia and oxidoreductase signals. It further suggests that low SDHB levels indicative of impaired mitochondrial complex II function may be a shared element of these pheochromocytomas. SDHB may thus constitute a marker for tumors with abnormal hypoxic profile.
AB - Pheochromocytomas and paragangliomas are neural-crest-derived tumors that arise from mutations in RET, VHL, NF1, and in the genes-encoding succinate dehydrogenase (SDH) subunits B (SDHB), C (SDHC), and D (SDHD). Despite their genetic diversity, these tumors cannot be clearly distinguished on the basis of their primary mutation. We recently identified two major transcriptional programs embedded within familial and sporadic pheochromocytomas and paragangliomas using global expression profiling. This review will summarize the major results of these studies and discuss their implications. The transcription data revealed that: (a) tumors with mutations in VHL, SDHB, and SDHD genes share a transcription signature of hypoxia, angiogenesis, and oxidoreductase imbalance; (b) SDHB protein is suppressed in tumors with mutations in SDHB and SDHD, and also in a subset of tumors with VHL mutations; and (c) HIF1α is involved in the SDHB downregulation observed in these tumors. These results are consistent with the existence of a close interconnection between the VHL and SDH pathways mediated predominantly by hypoxia and oxidoreductase signals. It further suggests that low SDHB levels indicative of impaired mitochondrial complex II function may be a shared element of these pheochromocytomas. SDHB may thus constitute a marker for tumors with abnormal hypoxic profile.
KW - Hypoxia
KW - Hypoxia-inducible factor (HIF)
KW - Hypoxia-inducible factor subunit
KW - Microarray
KW - Multiple endocrine neoplasia Type 2 (MEN 2)
KW - Mutation
KW - Neurofibromatosis Type 1 (NF1)
KW - Oxidative stress
KW - Oxidoreductase
KW - Paraganglioma
KW - Pathway intersection
KW - Pheochromocytoma
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UR - http://www.scopus.com/inward/citedby.url?scp=33845510751&partnerID=8YFLogxK
U2 - 10.1196/annals.1353.023
DO - 10.1196/annals.1353.023
M3 - Conference contribution
C2 - 17102089
AN - SCOPUS:33845510751
SN - 1573315974
SN - 9781573315975
T3 - Annals of the New York Academy of Sciences
SP - 208
EP - 220
BT - Pheochromocytoma
PB - Blackwell Publishing Inc.
ER -