Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB.
Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegetables, is known to be a potent inducer of the detoxification enzyme, NAD(P)H: quinone reductase (QR). QR catalyzes a two-electron transfer to a wide variety of redox-cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer risk. The upstream signaling mechanisms that lead to the induction of QR remain unclear. The 5' promoter region of the human QR gene contains the cis-acting AP-1 and NFkappaB transcription factor binding sites. When HT29 human colon cells were exposed to 25microM benzyl isothiocyanate, AP-1 binding increased, beginning at 3 hours and increasing until 16 hours. NFkappaB binding also increased, reaching a maximum at around 6 hours. We also found that c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The temporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity.
Patten
E J
EJ
Graduate Division of Biological and Biomedical Sciences, Department of Environmental and Occupational Health, School of Public Health, Emory University, 1518 Clifton Road, Atlanta, Georgia 30322, USA.
DeLong
M J
MJ
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D007527:Isoenzymes; D017879:Isothiocyanates; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; C031403:benzyl isothiocyanate; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases