Genetic networks of cooperative redox regulation of osteopontin.
Osteopontin is a primary cytokine and matrix-associated protein involved in medial thickening and neointima formation. Osteopontin binds integrin receptors, activates cell migration and matrix metalloproteinases, and mediates arteriosclerotic lesion formation and vessel calcification. To understand the complex biology of osteopontin, computational methodology was employed to identify sets of genes whose transcriptional states were predictive of osteopontin gene expression based on the transcriptional states of 12,400 genes and ESTs across 235 independent Affymetrix Murine Genome Array MG_U74Av2 hybridizations. Arginase [GenBank: U51805] and Mac-2 antigen [GenBank: X16834] were identified as primary attractors within the gene-gene interaction network of osteopontin. Resolution of molecular interactions among these genes indicated that the majority of predictor genes could be linked through redox regulated transcription by nuclear factor kappa-B and transforming growth factor beta inducible early gene 1 regulatory elements. Subsequent molecular analyses established redox sensitivity of a 200 bp region within the 5' UTR of opn promoter and implicated nuclear factor kappa-B and transforming growth factor beta inducible early gene 1 cis-acting elements in the regulation of osteopontin.
Partridge
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Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
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Ramos
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D000465:Algorithms; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001119:Arginase / Q000235:genetics; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D020224:Expressed Sequence Tags; D037502:Galectin 3 / Q000235:genetics; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000975:Antioxidants; D004268:DNA-Binding Proteins; D037502:Galectin 3; C491385:Klf10 protein, rat; D016328:NF-kappa B; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D006861:Hydrogen Peroxide; D001119:Arginase