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.
Lee
Sungwoo
S
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nakamura
Eijiro
E
Yang
Haifeng
H
Wei
Wenyi
W
Linggi
Michelle S
MS
Sajan
Mini P
MP
Farese
Robert V
RV
Freeman
Robert S
RS
Carter
Bruce D
BD
Kaelin
William G
WG
Schlisio
Susanne
S
D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000235:genetics*; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000378:metabolism; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D010673:Pheochromocytoma / Q000201:enzymology* / Q000235:genetics*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000254:growth & development; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins; D020932:Nerve Growth Factor; D011393:Procollagen-Proline Dioxygenase; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D013385:Succinate Dehydrogenase; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C490190:EGLN1 protein, human; C488894:EGLN3 protein, human; C497446:VHL protein, human