https://scholars.lib.ntu.edu.tw/handle/123456789/523727
標題: | Modulation of the expression of the invasion-suppressor CRMP-1 by cyclooxygenase-2 inhibition via reciprocal regulation of Sp1 and C/EBPα | 作者: | Wu C.-C. Lin J.-C. Yang S.-C. Lin C.-W. Chen J.J.W. JIN-YUAN SHIH Hong T.-M. PAN-CHYR YANG |
公開日期: | 2008 | 卷: | 7 | 期: | 6 | 起(迄)頁: | 1365-1375 | 來源出版物: | Molecular Cancer Therapeutics | 摘要: | 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/EBPα sites. Site-directed mutagenesis and deletion analysis revealed that the two C/EBPα 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/EBPα site, which overlaps with a Sp1 site. Overexpression of Sp1 decreased CRMP-1 promoter activity and protein expression, whereas overexpression of C/EBPα produced the opposite effect. Chromatin immunoprecipitation assays confirmed that Sp1 and C/EBPα compete for binding at the overlapping C/EBPα 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/EBPα and Sp1. COX-2 inhibitors increase CRMP-1 expression by inhibiting Sp1-DNA complex formation and enhancing DNA binding of C/EBPα at the promoter. Copyright ? 2008 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-49849101477&doi=10.1158%2f1535-7163.MCT-08-0091&partnerID=40&md5=85667c0b9220de43e1832fd6d98abbab https://scholars.lib.ntu.edu.tw/handle/123456789/523727 |
ISSN: | 1535-7163 | DOI: | 10.1158/1535-7163.MCT-08-0091 | SDG/關鍵字: | beta actin; CCAAT enhancer binding protein alpha; celecoxib; collapsin response mediator protein 1; cyclooxygenase 2; cyclooxygenase 2 inhibitor; glyceraldehyde 3 phosphate dehydrogenase; messenger RNA; nucleotide; transcription factor Sp1; transcription factor Sp3; tubulin; tumor suppressor protein; unclassified drug; CCAAT enhancer binding protein alpha; CRMP1 protein, human; cyclooxygenase 2; DNA; nerve protein; PTGS2 protein, human; transcription factor Sp1; 5' untranslated region; article; binding site; chromatin immunoprecipitation; complex formation; controlled study; CRMP 1 gene; enzyme inhibition; gel mobility shift assay; gene deletion; gene expression regulation; human; human cell; priority journal; promoter region; protein DNA binding; protein expression; protein protein interaction; site directed mutagenesis; transcription regulation; tumor suppressor gene; cancer invasion; DNA responsive element; genetic transcription; genetics; metabolism; molecular genetics; nucleotide sequence; pathology; protein binding; tumor cell line; upregulation; Base Sequence; CCAAT-Enhancer-Binding Protein-alpha; Cell Line, Tumor; Cyclooxygenase 2; DNA Mutational Analysis; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Neoplasm Invasiveness; Nerve Tissue Proteins; Protein Binding; Response Elements; Sp1 Transcription Factor; Transcription, Genetic; Up-Regulation |
顯示於: | 醫學系 |
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