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標題: Modulation of the expression of the invasion-suppressor CRMP-1 by cyclooxygenase-2 inhibition via reciprocal regulation of Sp1 and C/EBP alpha
作者: Wu, C.C.
Lin, J.C.
Yang, S.C.
Lin, C.W.
Chen, J.J.W.
Shih, J.Y.
Hong, T.M.
Yang, P.C.
關鍵字: response mediator protein-1;growth-factor expression;smooth-muscle-cells;colon-cancer cells;lung-cancer;metastasis-suppressor;p21(waf1/cip1) transcription;matrix;metalloproteinase-2;colorectal-cancer;pancreatic-cancer
Project: Molecular Cancer Therapeutics
期刊/報告no:: Molecular Cancer Therapeutics, Volume 7, Issue 6, Page(s) 1365-1375.
Collapsin response mediator protein-1 (CRMP-1) controls neural development and axonal growth but also acts as a cancer invasion suppressor. In this study, we investigated the transcriptional regulation of CRMP-1 expression. Using a serial deletion strategy, we identified a basal promoter region between nucleotides -100 and -180 in the 5' flanking region of CRMP-1 (nucleotides -1,920 to +50) that contains multiple putative Sp1 and C/EBP alpha sites. Site-directed mutagenesis and deletion analysis revealed that the two C/EBP alpha sites, from nucleotides -122 to -133 and from nucleotides -101 to -113, are the most important regulatory elements. Gel-shift and antibody supershift assays showed that Sp1 protein was also present at this C/EBP alpha site, which overlaps with a Sp1 site. Overexpression of Sp1 decreased CRMP-1 promoter activity and protein expression, whereas overexpression of C/EBP alpha produced the opposite effect. Chromatin immunoprecipitation assays confirmed that Sp1 and C/EBP alpha compete for binding at the overlapping C/EBP alpha and Sp1 sites and reciprocally regulate CRMP-1 expression. Overexpression of cyclooxygenase-2 (COX-2) decreased CRMP-1 mRNA and protein expression. Conversely, the COX-2 inhibitor, celecoxib, induced a dose-dependent increase in CRMP-1 expression. COX-2 inhibition also decreased Sp1-DNA complex formation and inhibited cell invasion. We conclude that transcription of the invasion suppressor, CRMP-1, is reciprocally regulated at the promoter region by C/EBP alpha and Sp1. COX-2 inhibitors increase CRMP-1 expression by inhibiting Sp1-DNA complex formation and enhancing DNA binding of C/EBP alpha at the promoter.
ISSN: 1535-7163
DOI: 10.1158/1535-7163.mct-08-0091
Appears in Collections:生物醫學研究所

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