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Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression.

Abstract
Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) of sympathetic neurons. Regressing tumor cells express high levels of the nerve growth factor (NGF) receptors TRKA and p75NTR and are dependent on NGF for survival; however, the underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor that is directly targeted by p53 family members, is highly expressed in favorable NBs. NGF withdrawal strongly upregulated UNC5D, E2F1, and p53 in human primary favorable NBs. The induced UNC5D was cleaved by caspases 2/3, and the released intracellular fragment translocated into the nucleus and interacted with E2F1 to selectively transactivate the proapoptotic target gene. The cleavage of UNC5D and its induction of apoptosis were strongly inhibited by addition of netrin-1. Unc5d(-/-) mice consistently exhibited a significant increase in dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons compared with wild-type cells. Our data suggest that UNC5D forms a positive feedback loop with p53 and E2F1 to promote NGF dependence-mediated PCD during NB regression.
AuthorsYuyan Zhu, Yuanyuan Li, Seiki Haraguchi, Meng Yu, Miki Ohira, Toshinori Ozaki, Atsuko Nakagawa, Toshikazu Ushijima, Eriko Isogai, Haruhiko Koseki, Yohko Nakamura, Cuize Kong, Patrick Mehlen, Hirofumi Arakawa, Akira Nakagawara
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 7 Pg. 2935-47 (Jul 2013) ISSN: 1558-8238 [Electronic] United States
PMID23778138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Nerve Growth Factors
  • Receptors, Cell Surface
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • UNC5H4 protein, human
  • netrin-1
  • Nerve Growth Factor
  • CASP2 protein, human
  • CASP3 protein, human
  • Caspase 2
  • Caspase 3
  • Cysteine Endopeptidases
Topics
  • Active Transport, Cell Nucleus
  • Animals
  • Apoptosis
  • Caspase 2 (metabolism)
  • Caspase 3 (metabolism)
  • Cysteine Endopeptidases (metabolism)
  • E2F1 Transcription Factor (metabolism)
  • Feedback, Physiological
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Regression, Spontaneous
  • Nerve Growth Factor (physiology)
  • Nerve Growth Factors (metabolism)
  • Neuroblastoma (metabolism, mortality, pathology)
  • PC12 Cells
  • Prognosis
  • Proteolysis
  • Rats
  • Receptors, Cell Surface (genetics, metabolism)
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 (metabolism)
  • Tumor Suppressor Proteins (metabolism)
  • Up-Regulation

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