Neopterin derivatives together with cyclic guanosine monophosphate induce c-fos gene expression.
We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a luminol-dependent chemiluminescence assay and strengthens toxicity of these agents against bacteria at slightly alkaline pH (pH 7.5), while 7,8-dihydroneopterin was shown to be a scavenger independent of the pH value. Besides various oxidants, phenolic antioxidants were shown to specifically induce expression of the c-fos and c-jun mRNAs. Using an inducible cfosCAT reporter transactivation system we studied the function of the pteridine derivatives on c-fos transactivation. For the first time, we demonstrate that neopterin and 7,8-dihydroneopterin, particularly together with cyclic guanosine monophosphate, induce c-fos gene expression. In humans, interferon-gamma induces the release of neopterin and 7,8-dihydroneopterin and also the synthesis of nitric oxide radical which in turn stimulate the formation of cGMP. Thus, in certain situations all three substances, namely neopterin, 7,8-dihydroneopterin and cGMP, may be present locally and even in the circulation at the same time. Based on our findings this constellation would significantly enhance the risk of c-fos gene expression and therefore promote tumour growth and development.
Uberall
F
F
Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Werner-Felmayer
G
G
Schubert
C
C
Grunicke
H H
HH
Wachter
H
H
Fuchs
D
D
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D006152:Cyclic GMP / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D019798:Neopterin / Q000031:analogs & derivatives; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D011621:Pteridines; C000976:7,8-dihydroneopterin; D001708:Biopterins; D015240:Phorbol 12,13-Dibutyrate; D019798:Neopterin; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C; D006152:Cyclic GMP