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Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer.

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.

Pubmed ID: 16098468

Authors

  • Lee S
  • Nakamura E
  • Yang H
  • Wei W
  • Linggi MS
  • Sajan MP
  • Farese RV
  • Freeman RS
  • Carter BD
  • Kaelin WG
  • Schlisio S

Journal

Cancer cell

Publication Data

August 15, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK065969
  • Agency: NINDS NIH HHS, Id: R01 NS034400

Mesh Terms

  • Adrenal Gland Neoplasms
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Dioxygenases
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Immediate-Early Proteins
  • Mutation
  • Nerve Growth Factor
  • Neurons
  • Pheochromocytoma
  • Procollagen-Proline Dioxygenase
  • Protein Kinase C
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Signal Transduction
  • Succinate Dehydrogenase
  • Sympathetic Nervous System
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein