Abstract
Germline NF1, c-RET, SDH, and VHL mutations cause familial pheochromocytoma. Pheochromocytomas derive from sympathetic neuronal precursor cells. Many of these cells undergo c-Jun-dependent apoptosis during normal development as NGF becomes limiting. NF1 encodes a GAP for the NGF receptor TrkA, and NF1 mutations promote survival after NGF withdrawal. We found that pheochromocytoma-associated c-RET and VHL mutations lead to increased JunB, which blunts neuronal apoptosis after NGF withdrawal. We also found that the prolyl hydroxylase EglN3 acts downstream of c-Jun and is specifically required among the three EglN family members for apoptosis in this setting. Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenal Gland Neoplasms / enzymology*
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Adrenal Gland Neoplasms / genetics*
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Apoptosis*
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins / metabolism
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Dioxygenases
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Immediate-Early Proteins / metabolism
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Mutation
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Nerve Growth Factor / metabolism
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Neurons / enzymology
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Pheochromocytoma / enzymology*
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Pheochromocytoma / genetics*
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Procollagen-Proline Dioxygenase / metabolism*
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / genetics
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Signal Transduction
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Succinate Dehydrogenase / metabolism
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Sympathetic Nervous System / cytology
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Sympathetic Nervous System / growth & development
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics*
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Ubiquitin-Protein Ligases / genetics*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Immediate-Early Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-jun
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Transcription Factors
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Tumor Suppressor Proteins
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endothelial PAS domain-containing protein 1
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Nerve Growth Factor
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Dioxygenases
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EGLN1 protein, human
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Procollagen-Proline Dioxygenase
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EGLN3 protein, human
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Succinate Dehydrogenase
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Protein Kinase C
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VHL protein, human