title: 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.
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Seiki
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Meng
authors.initials: M
authors.lastname: Yu
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
authors.forename: Eriko
authors.initials: E
authors.lastname: Isogai
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Cuize
authors.initials: C
authors.lastname: Kong
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009365:Neoplasm Regression, Spontaneous; D020932:Nerve Growth Factor / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D009447:Neuroblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016716:PC12 Cells; D011379:Prognosis; D059748:Proteolysis; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C529231:UNC5D protein, human; D000075388:Netrin-1; D020932:Nerve Growth Factor; C490360:CASP2 protein, human; C505407:CASP3 protein, human; D053143:Caspase 2; D053148:Caspase 3; D003546:Cysteine Endopeptidases