Identification of UNC5A as a novel transcriptional target of tumor suppressor p53 and a regulator of apoptosis.
UNC5A is an axon-guidance molecule, and plays a critical role in neuronal development and differentiation as a netrin-1 receptor. Emerging evidence suggests that axon guidance molecules including UNC5A regulate apoptosis in non-neuronal cells. Here, we report that UNC5A regulates apoptosis as a downstream target of p53. UNC5A expression was strongly induced by exogenous and endogenous p53. Chromatin immunoprecipitation (ChIP) revealed that p53 binds to a sequence in the promoter region of the UNC5A gene. Reporter assays showed that this sequence exhibits p53-dependent transcriptional activity. Overexpression of UNC5A significantly suppressed colony formation of two glioblastoma cell lines-U373MG and T98G. UNC5A dramatically induced apoptosis through the activation of caspase-3 in various cancer cell lines, including LS174T (colon cancer), U373MG (glioblastoma), SH-SY5Y (neuroblastoma), and SKNAS (neuroblastoma). Finally, gamma irradiation strongly induced the expression of UNC5A mRNA in the spleen and colon of p53+/+ mice, but not in those of p53-/- mice, implying that the transcription of UNC5A in vivo is regulated by p53. These results suggest that UNC5A is a novel transcriptional target of p53 and plays a role in p53-dependent apoptosis.
Miyamoto
Yuji
Y
Cancer Medicine and Biophysics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Futamura
Manabu
M
Kitamura
Noriaki
N
Nakamura
Yasuyuki
Y
Baba
Hideo
H
Arakawa
Hiroufmi
H
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D000075386:Netrin Receptors; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000617308:Unc5A protein, mouse