Article

Genomic analysis of stress response genes.

Syngenta Central Toxicology Laboratory, Alderley Park, SK10 4TJ, Cheshire, UK.
Toxicology Letters (Impact Factor: 3.15). 05/2003; 140-141:149-53. DOI: 10.1016/S0378-4274(02)00501-5
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
74 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, a series of exciting reports have revealed that terminally differentiated somatic cells can be reprogrammed to generate induced pluripotent stem (iPS) cells via overexpression of a cocktail of transcription factors such as Oct3, Sox2, Klf4, and c-Myc or Oct3, Sox2, Nanog, and Lin28. Most recently, these iPS cells has been used to generate viable, live-born progeny by tetraploid complementation. Reprogramming of iPS cells inaugurates a new era of biology and medicine, it inevitably brings new challenges, e.g., how these factors induce reprogramming and how their expression is regulated. To facilitate iPS cell research, this review focuses on how expression and activation of these transcription factors are regulated.
    Biochemical and Biophysical Research Communications 11/2009; 390(4):1081-6. · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: WD-40 repeat proteins play important roles in a variety of cellular functions, such as cell growth, proliferation, apoptosis and intracellular signal transduction. We previously identified a novel member of this family, WDR26. To examine the biological function of WDR26, we used hWDR26 plasmids and antisense phosphorothioate oligodeoxynucleotides (asODNs) against WDR26 to examine its role in response to oxidative stress in human SH-SY5Y neuroblastoma cells. Our results showed that H2O2 at 0.5mM substantially induced cell death and significantly up-regulated the WDR26 expression, and WDR26 over-expression in turn strongly suppressed H2O2-induced cell death. Moreover, asODNs markedly inhibited the de novo biosynthesis of WDR26, which contributed to enhanced cell death induced by H2O2. Finally, we found that WDR26 over-expression also down-regulated the transcriptional activity of AP-1 during H2O2-induced SH-SY5Y cell death. Taken together, these results indicated that WDR26 was up-regulated by oxidative stress and played a key role in H2O2-induced SH-SY5Y cell death, which may be mediated by the down-regulation of AP-1 transcriptional activity.
    Neuroscience Letters 06/2009; 460(1):66-71. · 2.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stimulation of the mouse hindlimb via the sciatic nerve was performed for a 4-h period to investigate acute muscle gene activation in a model of muscle phenotype conversion. Initial force production (1.6 +/- 0.1 g/g body wt) declined 45% within 10 min and was maintained for the remainder of the experiment. Force returned to initial levels upon study completion. An immediate-early growth response was present in the extensor digitorum longus (EDL) muscle (FOS, JUN, activating transcription factor 3, and musculoaponeurotic fibrosarcoma oncogene) with a similar but attenuated pattern in the soleus muscle. Transcript profiles showed decreased fast fiber-specific mRNA (myosin heavy chains 2A and 2B, fast troponins T(3) and I, alpha-tropomyosin, muscle creatine kinase, and parvalbumin) and increased slow transcripts (myosin heavy chain-1beta/slow, troponin C slow, and tropomyosin 3y) in the EDL versus soleus muscles. Histological analysis of the EDL revealed glycogen depletion without inflammatory cell infiltration in stimulated versus control muscles, whereas ultrastructural analysis showed no evidence of myofiber damage after stimulation. Multiple fiber type-specific transcription factors (tea domain family member 1, nuclear factor of activated T cells 1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta, circadian locomotor output cycles kaput, and hypoxia-inducible factor-1alpha) increased in the EDL along with transcription factors characteristic of embryogenesis (Kruppel-like factor 4; SRY box containing 17; transcription factor 15; PBX/knotted 1 homeobox 1; and embryonic lethal, abnormal vision). No established in vivo satellite cell markers or genes activated in our parallel experiments of satellite cell proliferation in vitro (cyclins A(2), B(2), C, and E(1) and MyoD) were differentially increased in the stimulated muscles. These results indicated that the molecular onset of fast to slow phenotype conversion occurred in the EDL within 4 h of stimulation without injury or satellite cell recruitment. This conversion was associated with the expression of phenotype-specific transcription factors from resident fiber myonuclei, including the activation of nascent developmental transcriptional programs.
    AJP Cell Physiology 08/2009; 297(3):C556-70. · 3.71 Impact Factor

Full-text

Download
1 Download
Available from