| Budget Amount *help |
¥3,370,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
When A549 human pulmonary epithelial cells were exposed to sodium metavanadate (NaVO3) , the pentavalent species of vanadium, phosphorylation of p53 protein at Ser15 and accumulation of total p53 protein were found in a time (8-48 hr) - and dose (10-200 μM) -dependent manner. Among serines in p53 protein immunoprecipitated from A549 cells treated with 100 μM NaVO3 for 48 hr, only Ser15 was markedly phosphorylated. Treatment with other vanadate compounds, sodium orthovanadate (Na3VO4) and ammonium metavanadate (NH4VO3) , also induced Serl5 phosphorylation and accumulation of p53 protein. While phosphorylation of extracellular signal-regulated protein kinase (ERK) was found in cells treated with NaVO3, treatment with U0126 did not suppress Serl5 phosphorylation. On the other hand, treatment with wortmannin or caffeine, the inhibitors to phosphatidylinositol 3-kinase related kinases (PIKKs) , suppressed NaVO3-induced Ser15 phosphorylation of p53 protein. The silencing of ataxia t
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elangiectasia mutated (ATM) expression using short-interference RNA resulted in the marked suppression of Ser15 phosphorylation in A549 cells exposed to NaVO3. However, treatment with antioxidants such as catalase and N-acetylcysteine did not suppress NaVO3-induced Ser15 phosphorylation. Transcriptional activation of p53 and DNA fragmentation in A549 cells treated with NaVO3 were suppressed only slightly by S15A mutation, suggesting that Ser15 phosphorylation is not essential for these responses. The present results showed that vanadate induces the phosphorylation of p53 at Ser15 depending on ATM, one of the members of PIKK family, in A549 cells. In addition, similar Ser15 phosphorylation of p53 protein was found in SH-SY5Y cells exposed to acrylamide and A549 cells exposed to zinc. In renal proximal tubular cells exposed to cadmium, signal transducers and activators of transcription (Stats) , a family of latent cytoplasmic transcription factors, were found to be phosphorylated at Ser727. Less
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