Pharmacologic profiling of transcriptional targets deciphers promoter logic
| Autor: | Irene Collins, D H Stewart, Dennis D. Taub, W J Freebern, M C McNutt, H A Biebuyck, Idalia Montano, A Graham, Kevin Gardner, G V R Chandramouli, Cynthia M. Haggerty |
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| Rok vydání: | 2005 |
| Předmět: |
Time Factors
Transcription Genetic T-Lymphocytes Computational biology Biology Lymphocyte Activation Transfection Jurkat Cells CD28 Antigens Genes Reporter Cyclosporin a Genetics Transcriptional regulation Humans Immunologic Factors Insulin-Like Growth Factor I Promoter Regions Genetic Cells Cultured Oligonucleotide Array Sequence Analysis Pharmacology Regulation of gene expression Principal Component Analysis Models Genetic Gene Expression Profiling Gene targeting Gene expression profiling AP-1 transcription factor Gene Expression Regulation Regulatory sequence Gene Targeting Interleukin-2 Molecular Medicine Mitogens Signal transduction Algorithms Signal Transduction |
| Zdroj: | The Pharmacogenomics Journal. 5:305-323 |
| ISSN: | 1473-1150 1470-269X |
| DOI: | 10.1038/sj.tpj.6500325 |
| Popis: | The blueprint for cellular diversity and response to environmental change is encoded in the cis-acting regulatory sequences of most genes. Deciphering this 'cis-regulatory code' requires multivariate data sets that examine how these regions coordinate transcription in response to diverse environmental stimuli and therapeutic treatments. We describe a transcriptional approach that profiles the activation of multiple transcriptional targets against combinatorial arrays of therapeutic and signal transducing agents. Application of this approach demonstrates how cis-element composition and promoter context combine to influence transcription downstream of mitogen-induced signaling networks. Computational dissection of these transcriptional profiles in activated T cells uncovers a novel regulatory synergy between IGF-1 and CD28 costimulation that modulates NF-kappaB and AP1 pathways through signaling cascades sensitive to cyclosporin A and wortmannin. This approach provides a broader view of the hierarchical signal integration governing gene expression and will facilitate a practical design of combinatorial therapeutic strategies for exploiting critical control points in transcriptional regulation. |
| Databáze: | OpenAIRE |
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