Copper-inducible transcription: regulation by metal- and oxidative stressresponsive pathways

2004 ◽  
Vol 286 (2) ◽  
pp. C293-C301 ◽  
Author(s):  
Michael D. Mattie ◽  
Jonathan H. Freedman

Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.

1999 ◽  
Vol 341 (2) ◽  
pp. 363-369 ◽  
Author(s):  
Flavio FLAMIGNI ◽  
Annalisa FACCHINI ◽  
Cristina CAPANNI ◽  
Claudio STEFANELLI ◽  
Benedetta TANTINI ◽  
...  

The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the induction of ornithine decarboxylase (ODC) was investigated by using PD98059, a specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction inhibitors. In D,L-α-difluoromethylornithine (DFMO)-resistant L1210 cells stimulated to grow from quiescence, treatment with PD98059 inhibited p44/42 MAPK phosphorylation and the induction of ODC activity and protein. A marked reduction of the accumulation of mature ODC mRNA and its intron-containing precursor was observed, whereas ODC turnover was hardly affected. PD98059 also reduced the content of antizyme, but not that of antizyme mRNA. U0126, a novel and more potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction at lower concentrations with respect to PD98059. Other effective inhibitors of ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the involvement of other key proteins of signal-transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which may have a positive impact on MAPK. Cells kept in a DFMO-free medium, and thus containing high levels of putrescine and spermidine, showed enhanced MAPK phosphorylation and lower sensitivity to PD98059, compared with cells maintained in the presence of DFMO. In conclusion, these results indicate that the activation of p44/42 MAPK may favour the expression of ODC, and that polyamines, in turn, may affect the phosphorylation state of MAPK.


2000 ◽  
Vol 20 (17) ◽  
pp. 6426-6434 ◽  
Author(s):  
Lori A. Neely ◽  
Charles S. Hoffman

ABSTRACT A significant challenge to our understanding of eukaryotic transcriptional regulation is to determine how multiple signal transduction pathways converge on a single promoter to regulate transcription in divergent fashions. To study this, we have investigated the transcriptional regulation of theSchizosaccharomyces pombe fbp1 gene that is repressed by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway and is activated by a stress-activated mitogen-activated protein kinase (MAPK) pathway. In this study, we identified and characterized twocis-acting elements in the fbp1 promoter required for activation of fbp1 transcription. Upstream activation site 1 (UAS1), located approximately 900 bp from the transcriptional start site, resembles a cAMP response element (CRE) that is the binding site for the atf1-pcr1 heterodimeric transcriptional activator. Binding of this activator to UAS1 is positively regulated by the MAPK pathway and negatively regulated by PKA. UAS2, located approximately 250 bp from the transcriptional start site, resembles a Saccharomyces cerevisiae stress response element. UAS2 is bound by transcriptional activators and repressors regulated by both the PKA and MAPK pathways, although atf1 itself is not present in these complexes. Transcriptional regulation offbp1 promoter constructs containing only UAS1 or UAS2 confirms that the PKA and MAPK regulation is targeted to both sites. We conclude that the PKA and MAPK signal transduction pathways regulatefbp1 transcription at UAS1 and UAS2, but that the antagonistic interactions between these pathways involve different mechanisms at each site.


2009 ◽  
Vol 02 (01) ◽  
pp. 93-100 ◽  
Author(s):  
LING ZHU ◽  
TIMON CHENG-YI LIU ◽  
MIN WU ◽  
JIAN-QIN YUAN ◽  
TONG-SHENG CHEN

Photobiomodulation (PBM) is a modulation of monochromatic light or laser irradiation (LI) on biosystems. It is reviewed from the viewpoint of extraocular phototransduction in this paper. It was found that LI can induce extraocular phototransduction, and there may be an exact correspondence relationship of LI at different wavelengths and in different dose zones, and cellular signal transduction pathways. The signal transduction pathways can be classified into two types so that the Gs protein-mediated pathways belong to pathway 1, and the other pathways such as protein kinase Cs -mediated pathways and mitogen-activated protein kinase-mediated pathways belong to pathway 2. Almost all the present pathways found to mediate PBM belong to pathway 2, but there should be a pathway 1-mediated PBM. The previous studies were rather preliminary, and therefore further work should be done.


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