Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 7, Pages 2935-2947Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65988
Keywords
-
Categories
Funding
- Ministry of Health, Labor, and Welfare of Japan
- Takeda Science Foundation
- National Cancer Center Research and Development Fund
- Ministry of Education, Culture, Sports, Science and Technology of Japan (JSPS KAKENHI) [19591271, 24249061, 21591378, 24591566]
- Grants-in-Aid for Scientific Research [19591271, 24591566, 21591378, 23591562, 23501278, 23249015] Funding Source: KAKEN
Ask authors/readers for more resources
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 p75(NTR) 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 proapoptodc 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available