Different mechanisms are responsible for c-jun mRNA induction by cisplatin and ultraviolet light.
Ultraviolet light (UV) and different DNA-damaging agents are known to induce AP-l-transcription-factor activity. Whereas UV induction appears to be triggered by events at the cell membrane, the mechanism of AP-l activation by alkylating or platinating agents is not known. We have here examined the effect of cisplatin on AP-l activity in RPMI-8322 melanoma cells. Cisplatin was found to induce binding of nuclear proteins to TRE elements from the c-jun and collagenase-gene promoters, and was also found to induce activation of a c-jun-promoter reporter construct. Compared with stimulation by UV, cisplatin stimulation of c-jun-promoter activity was found to be less sensitive to a dominant negative mutant of Raf-I protein kinase. Furthermore, whereas UV treatment resulted in strong MAP-kinase activation, cisplatin treatment resulted only in a weak and transient increase. These data suggest that the Raf-MAPK pathway is of minor importance for the induction of c-jun-promoter activity by cisplatin. Finally, we report that cisplatin induction of c-jun in RPMI-8322 cells was blocked by herbimycin A, an inhibitor of Src-family tyrosine kinases. In contrast, UV induction of c-jun was not blocked by herbimycin A. In conclusion, our data strongly suggest that UV and cisplatin induction of c-jun mRNA in RPMI-8322 melanoma cells occur by distinct mechanisms.
Rabo
Y B
YB
Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden.
Shoshan
M C
MC
Linder
S
S
Hansson
J
J
D016227:Benzoquinones; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D016758:Genes, jun / Q000187:drug effects* / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D017828:Rifabutin / Q000031:analogs & derivatives; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D011518:Proto-Oncogene Proteins; D011809:Quinones; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002945:Cisplatin