Abstract
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-κB 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.
Original language | English (US) |
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Pages (from-to) | 305-323 |
Number of pages | 19 |
Journal | Pharmacogenomics Journal |
Volume | 5 |
Issue number | 5 |
DOIs | |
State | Published - 2005 |
Externally published | Yes |
Keywords
- Cyclosporin A
- IGF-1
- Multivariate analysis
- Promoter structure
- Signal transduction
- Transcription regulation
- Transcriptional profiling
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Pharmacology