title: An overview of transcriptional regulation in response to toxicological insult.
abstract: The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3/1, 6020 Innsbruck, Austria. paul.jennings@i-med.ac.at
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
authors.forename: Alice
authors.initials: A
authors.lastname: Limonciel
authors.forename: Luca
authors.initials: L
authors.lastname: Felice
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D018384:Oxidative Stress / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D043922:Toxicogenetics / Q000379:methods; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D050791:STAT Transcription Factors; D015262:Xenobiotics