| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Yuko Chiba Cancer Center Research Institute, Department of Biochemistry, Research Fellow, 研究局・生化学研究部, 研究員 (60260254)
KAGEYAMA Hajume Chiba Cancer Center Research Institute, Department of Biochemistry, Research Fellow, 研究局・生化学研究部, 研究員 (50260253)
OZAKI Toshinori Chiba Cancer Center Research Institute, Department of Biochemistry, Senior Investigator, 研究局・生化学研究部, 研究員 (40260252)
ISOGAI Eriko Chiba Cancer Center Research Institute, Department of Biochemistry, Research Fellow, 研究局・生化学研究部, 研究員 (40300917)
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| Research Abstract |
Translational research of the Primary neuroblastomas.
During the last 3 years, 600 samples of primary neuroblastoma have been sent to our laboratory and subjected to analysis of DNA ploidy, MYCN amplification, TrkA expression, 1p36 loss of heterozygosity. The results showed that a subset of neuroblastoma with a tendency to spontaneously regress had aneuploidy, single copy of MYCN, high levels of expression of TrkA and no loss of heterozygosity of 1p36. Especially, TrkA expression seemed to be one of the most important prognostic factors of neuroblastoma.
Molecular analysis of neuronal cell death in neuroblastoma cell lines.
The molecular mechanism of neuronal cell death which was induced by retinoic acid and was recued by the GDNF/Ret signaling was studied by using neuroblastoma cell line, CHP134. The results obtained were as follows. 1) Among the caspase family, only caspases-1, 3 and 9 were induced at both mRNA and protein levels. Only survivin among the IAP family molecules was induced
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. 2) In the p53 pathway, p21WAF1 was transiently induced, while other target genes such as Bax, PIG3 and Mdm2 were not. 3) Mitochondrial membrane potential was descreased. 4) The cell death was inhibited by activation of GDNF/NTN signaling. Thus, the retinoic acid-induced neuronal cell death appeared to be mediated by the activation of mitochondria 【thermodynamics】 caspases-9 and 3 pathway.
Functional role of survivin
Our previous study has suggested that survivin mapped to 17q25 is one of the candidate genes of the 17q gain which is often observed in advanced stages neuroblastomas. We found a novel splice variant, survivin-b, with insertion within the functional BIR domain. It was thought to be a loss of function variant. Survivin-a and b competed to bind the microtubule in vitro, suggesting that both isoforms might regulate life and death of neuroblastoma cells.
Functional analysis of p73
Based on the kockout mice, p73 may function during embryonic development and regulate neuronal cell death. We found that COOH-terminal region of p73 regulated negatively the transactivation function of NH2-terminal region and positively the induction of apoptosis Less
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