Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression
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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.
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In absence of ligands, UNC5D and NTRK3 are subjected to CASP3 cleavage generating intracellular fragments that translocate either into nucleus to trigger E2F1-driven expression of pro-apoptotic genes (UNC5D) or at mitochondria to activate CASP9 upon MOMP (NTRK3).
“(4) UNC5D and NTRK3 are subjected to CASP3 cleavage generating intracellular fragments that translocate either into the nucleus to trigger the E2F transcription factor 1 (E2F1)-driven expression of pro-apoptotic genes (as in the case of UNC5D) or at mitochondria to activate CASP9 upon MOMP (as in the case of NTRK3) [358, 359].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [358]
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- Authors
- Zhu, Y., Li, Y., Haraguchi, S., Yu, M., Ohira, M., Ozaki, T., Nakagawa, A., Ushijima, T., Isogai, E., Koseki, H., Nakamura, Y., Kong, C., Mehlen, P., Arakawa, H., & Nakagawara, A.
- Affiliations
- Chiba Cancer Center Research Institute (JP)
- National Center For Child Health and Development (JP)
- National Cancer Center Research Institute (JP)
- RIKEN (JP)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Nakagawara, Akira
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-06-17
- Volume
- 123
- Issue
- 7
- Pages
- 2935-2947
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3696554
- OpenAlex
- W2109307498
- Cited by
- 57
- References
- 60
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 1 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 1 · 2014: 8 · 2013: 2
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (23501278, 21591378, 19591271, 23249015, 24249061, 24591566, 23591562)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- UNC5D, nerve growth factor withdrawal, dependence receptors, p53, E2F1, apoptosis, netrin-1, sympathetic neurons, TrkA, p75 neurotrophin receptor, caspase cleavage, dorsal root ganglia, programmed cell death
- MeSH terms
- Netrin-1, Animals, Cysteine Endopeptidases, Humans, Mice, Inbred C57BL, Neoplasm Regression, Spontaneous, Nerve Growth Factors, Neuroblastoma, Prognosis, Receptors, Cell Surface, Transcriptional Activation, Up-Regulation, Gene Expression, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, PC12 Cells, Apoptosis, Mice, Knockout, Nerve Growth Factor, Active Transport, Cell Nucleus, Feedback, Physiological, Tumor Suppressor Proteins, E2F1 Transcription Factor, Mice, Rats, Caspase 2, Caspase 3, Kaplan-Meier Estimate, Proteolysis
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