Dependence receptor UNC5D mediates nerve growth factor depletion–induced neuroblastoma regression

• DOI: 10.1172/jci65988
• Publication Date: 2013-06-16T10:00:18Z
• Authors: Yuyan 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
• Keywords: Feedback, Physiological; Mice, Knockout; 0301 basic medicine; Caspase 3; Active Transport, Cell Nucleus; Caspase 2; Gene Expression; Apoptosis; Kaplan-Meier Estimate; Netrin-1; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Cysteine Endopeptidases; Mice; Neuroblastoma; 03 medical and health sciences; Neoplasm Regression, Spontaneous; Nerve Growth Factor; Animals; Humans; Nerve Growth Factors; E2F1 Transcription Factor

Spontaneous regression of neuroblastoma (NB) resembles the developmentally regulated programmed cell death (PCD) sympathetic neurons. Regressing tumor cells express high levels nerve growth factor (NGF) receptors TRKA and p75NTR are dependent on NGF for survival; however, underlying molecular mechanism remains elusive. Here, we show that UNC5D, a dependence receptor is directly targeted by p53 family members, highly expressed in favorable NBs. withdrawal strongly upregulated E2F1, human primary The induced UNC5D was cleaved caspases 2/3, released intracellular fragment translocated into nucleus interacted with E2F1 to selectively transactivate proapoptotic target gene. cleavage its induction apoptosis were inhibited addition netrin-1. Unc5d(-/-) mice consistently exhibited significant increase dorsal root ganglia neurons resistance depletion-induced compared wild-type cells. Our data suggest forms positive feedback loop promote dependence-mediated PCD during NB regression.