| Budget Amount *help |
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Research Abstract |
To clarify the role of netrin-1 in an anti-apoptotic signaling pathway, we added the purified recombinant netrin 1 to the culture medium of the cells infected with adenovirus p53 (Ad-p53). In the absence of netrin-1, infection with Ad-p53 strongly induced apoptosis in the infected cells. However, an addition of the recombinant netrin-1 protein at the various concentrations (from 200ng/ml to 1000ng/ml) strikingly blocked p53-indced apoptosis. Under the condition, all the target genes including p21/WAF1, p53R2, and MDM2, as well as p53 protein itself were highly expressed in the cells, implying netrin-1 does not affect p53 activation and its transcriptional activity. On the other hand, all the caspases examined including caspase-9, caspase-8 and caspase-3 were completely inhibited by netrin-1. Therefore we concluded that netrin-1 anti-apoptotic signaling is likely to block the down-stream molecules of p53-dependent apoptotic pathway. Interestingly, we have found that an unidentified receptor mediates netrin-1 anti-apoptotic signaling pathway.
These results suggest that the netrin-1 anti-apoptotic signaling pathway probably causes carcinogenesis, cancer metastasis and tolerance of cancer cells to anti-cancer drugs. Therefore, we think that further analysis of the mechanism for the netrin-1 signaling in anti-cell death pathway and its alterations in human cancers could provide a new strategy for cancer therapy in the future.
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