Toxicogenomics for transcription factor-governed molecular pathways: moving on to roles beyond classification and predic
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Toxicogenomics for transcription factor-governed molecular pathways: moving on to roles beyond classification and prediction Melvin E. Andersen • Patrick D. McMullen Sudin Bhattacharya
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Received: 12 October 2012 / Accepted: 13 November 2012 / Published online: 25 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012
In this issue of Archives for Toxicology, Jennings et al. (2012) provide a review of transcriptional regulation associated with perturbation of a variety of biological pathways by chemicals. The review focuses on specific transcriptional regulatory networks activated by what the authors refer to as ‘‘transcription factor-governed molecular pathways.’’ We will use their terminology throughout our perspective. These pathways include the family of nuclear receptors, several stress-activated transcription factors, and two immunomodulatory transcription factors: STAT and NF-jB. One goal of knowing the specificity of transcriptomic responses from these pathways is development of biomarkers for the ‘‘transcription factor-governed pathway’’ that could support classification or early prediction of likely toxic responses of compounds. In addition to providing a thorough review of toxicogenomics of activation of these pathways, the paper provides two tables showing a sequential process for each pathway from activating events to alterations in transcript levels for target genes. For each pathway, ancillary information includes endogenous ligand, exogenous ligands, inhibitory complexes, DNA target sequences for transcription factor binding, and some target genes. These tables provide a wealth of information related to the context in which the transcription factors function to coordinate information flow from cell exposures to transcription factor-activating ligands/stressors to gene expression. The authors’ overview compresses a large amount of information about toxicogenomic responses to activators of transcription factorgoverned pathways in a readily digestible package, M. E. Andersen (&) P. D. McMullen S. Bhattacharya The Hamner Institutes for Health Research, Research Triangle Park, NC 27709-2137, USA e-mail: [email protected]
highlighting the significant advances in applying microarray technologies in toxicology. This perspective first notes the value of toxicogenomics in organizing information on transcription factor-governed pathways. We then look to a path forward in which toxicogenomics and other technologies will provide detailed knowledge on both the dose–response and structure and function of these transcription factor-governed pathways, thereby supporting a new generation of risk and safety assessment modalities based on cellular assays of the perturbations of these pathways.
Using specific chemical perturbations to evaluate pathway responses A simplified description of the transcription factor-governed pathways shows either stress-related or ligand-specific binding as an activating event (Fig. 1). The activated transcription factor (TF* in Fig. 1) then forms an appropria
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