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Claudin-5, an integral tight junction protein component, plays a critical role in permeability of the endothelial cell barrier. Recently, we have shown that claudin-5 protein is down-regulated by the proinflammatory cytokine TNF alpha and its levels restored by dexamethasone treatment. In order to investigate the regulation of claudin-5 at the transcriptional level, we have cloned the murine claudin-5 promoter. The claudin-5 promoter sequence (1131 bp) showed no consensus TATA-box. We identified putative transcription factor binding sites, including six full and two half sites degenerated glucocorticoid-response elements (GREs), two NFkappaB, three Sp1, one Sp2, one Ap2, as well as three E-boxes. Serially deleted promoter constructs showed high basal activity. TNF alpha significantly reduced the promoter activity and mRNA levels of claudin-5 in brain cEND and myocardial MyEND endothelial cells. Dexamethasone treatment led to a significant increase of the murine claudin-5 promoter activity and mRNA levels in cEND cells. However, no claudin-5 induction could be observed in MyEND cells in response to dexamethasone. Our studies suggest tissue-specific regulation of the claudin-5 gene via glucocorticoids and a high vulnerability of claudin-5 to TNF alpha. This could be an important mechanism in diseases accompanied by the release of proinflammatory cytokines, for example in patients with chronic heart failure or multiple sclerosis.
Pubmed ID: 18996436 RIS Download
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Genomatix is a privately held company that offers software, databases, and services aimed at understanding gene regulation at the molecular level representing a central part of systems biology. Its multilayer integrative approach is a working implementation of systems biology principles. Genomatix combines sequence analysis, functional promoter analysis, proprietary genome annotation, promoter sequence databases, comparative genomics, scientific literature data mining, pathway databases, biological network databases, pathway analysis, network analysis, and expression profiling into working solutions and pipelines. It also enables better understanding of biological mechanisms under different conditions and stimuli in the biological context of your data. Some of Genomatix'' most valuable assets are the strong scientific background and the years of experience in research & discovery as well as in development & application of scientific software. Their firsthand knowledge of all the complexities involved in the in-silico analysis of biological data makes them a first-rate partner for all scientific projects involving the evaluation of gene regulatory mechanisms. The Genomatix team has more than a decade of scientific expertise in the successful application of computer aided analysis of gene regulatory networks, which is reflected by more than 150 peer reviewed scientific publications from Genomatix'' scientists More than 35,000 researchers in industry and academia around the world use this technology. The software available in Genomatix are: - GenomatixSuite: GenomatixSuite is our comprehensive software bundle including ElDorado, Gene2Promoter, GEMS Launcher, MatInspector and MatBase. GenomatixSuite PE also includes BiblioSphere Pathway Edition. Chromatin IP Software - RegionMiner: Fast, extensive analysis of genomic regions. - ChipInspector: Discover the real power of your microarray data. Genome Annotation Software - ElDorado: Extended Genome Annotation. - Gene2Promoter: Retrieve & analyze promoters - GPD: The Genomatix Promoter Database, which is now included with Gene2Promoter. Knowledge Mining Software - BiblioSpere : The next level of pathway/genomics analysis. - LitInspector: Literature and pathway analysis for free. Sequence Analysis Software - GEMS Launcher: Our integrated collection of sequence analysis tools. - MalInspector: Search transcription factor binding sites - MatBase: The transcription factor knowledge base. Other (no registration required) Software - DiAlign: Multiple alignment of DNA/protein sequence. - Genomatix tools: Various small tools for sequence statistics, extraction, formatting, etc.
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