Pharmacologic profiling of transcriptional targets deciphers promoter logic

W. J. Freebern, C. M. Haggerty, I. Montano, M. C. McNutt, I. Collins, A. Graham, G. V.R. Chandramouli, D. H. Stewart, H. A. Biebuyck, D. D. Taub, K. Gardner

Research output: Contribution to journalArticle

11 Scopus citations

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 languageEnglish (US)
Pages (from-to)305-323
Number of pages19
JournalPharmacogenomics Journal
Volume5
Issue number5
DOIs
StatePublished - Oct 31 2005
Externally publishedYes

Keywords

  • Cyclosporin A
  • IGF-1
  • Multivariate analysis
  • Promoter structure
  • Signal transduction
  • Transcription regulation
  • Transcriptional profiling

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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  • Cite this

    Freebern, W. J., Haggerty, C. M., Montano, I., McNutt, M. C., Collins, I., Graham, A., Chandramouli, G. V. R., Stewart, D. H., Biebuyck, H. A., Taub, D. D., & Gardner, K. (2005). Pharmacologic profiling of transcriptional targets deciphers promoter logic. Pharmacogenomics Journal, 5(5), 305-323. https://doi.org/10.1038/sj.tpj.6500325