Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation
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概要
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<p><b>Background:</b> Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulinlikegrowth factors (IGF<sub>s</sub>) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 inhuman hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.<br /><b>Methods:</b> In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylationconstructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.<br />Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensussequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobilityshift assay that p53 binding to the promoter region was diminished when methylated.<br /><b>Conclusion:</b> From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression ofIGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.</p>
- BioMed Centralの論文
- 2005-01-20
BioMed Central | 論文
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