Genomic analysis of stress response genes
Jonathan G. Moggs*, George Orphanides
Syngenta Central Toxicology Laboratory, Alderley Park, Cheshire SK10 4TJ, UK
Received 15 September 2002; accepted 12 December 2002
Mammalian cells respond to a wide range of external stimuli including growth factors, peptide hormones, cytokines,
osmotic stress, heat shock, pharmacological agents and toxicants via multiple signalling pathways. Genome-wide
transcript profiling simultaneously monitors the gene expression programs downstream of all signal transduction
pathways and can identify novel molecular targets for stress-inducing signals. Our laboratory has combined transcript
profiling of cytotoxic compounds with experimental systems in which signalling components are disrupted (e.g. small
molecule protein kinase inhibitors) to reveal the contribution of specific signalling pathways to the transcriptional
response to toxicant-induced stress. A complementary approach for elucidating the molecular mechanisms that regulate
transcriptional responses to toxicants involves DNA sequence analysis of gene regulatory regions obtained via data
mining of recently completed mammalian genome sequences. Together, these approaches reveal the molecular
mechanisms used to finely tune alterations in gene expression, enabling cells to react in an appropriate manner to
external stress-inducing stimuli.
# 2003 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Stress response; Protein kinase; Signalling pathways; Gene regulation; Transcript profiling; Microarray
The exposure of a cell to external stimuli triggers
complex intracellular signalling cascades that re-
sult in finely tuned alterations in gene expression,
enabling the cell to react in an appropriate manner
via regulation of cell growth and division, differ-
entiation, metabolism and many other functions.
Individual stimuli can activate multiple signalling
pathways, including mitogen-activated protein
(MAP) kinases, inositol lipid signalling, nuclear
factor-kB, protein kinase C, intracellular Ca2?
release or signal transducers and activators of
transcription that produce phosphorylation-de-
pendent activation of transcription factors. These
recruit active transcription factor complexes to
upstream regulatory sequences of immediate-early
(IE) genes and initiate transcription by RNA
polymerase II. IE genes encode a range of proteins
that include transcription factors and cytokines,
and these in turn regulate secondary transcrip-
tional responses appropriate for the particular
stimulus to which a cell is exposed. Cellular
* Corresponding author. Tel.: ? /44-1625-519315; fax: ? /44-
Toxicology Letters 140?/141 (2003) 149?/153
0378-4274/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved.