Changes of the trans-activating potential of AP-1 transcription factor during cyclosporin A-induced apoptosis of glioma cells are mediated by phosphorylation and alterations of AP-1 composition.
Although the AP-1 transcription factor is known to play a role in cell proliferation and activation, it is also involved in apoptosis of cells in response to stress, DNA-damaging agents, or lack of survival signals. To understand how AP-1 might contribute to distinct biological processes, we tested a hypothesis that changes in AP-1 composition or phosphorylation state modulate its transcriptional activity during cyclosporin A-induced apoptosis of glioma cells. The induction of AP-1 DNA binding activity composed of c-Jun, JunB, JunD, and ATF-2 proteins preceded apoptosis. The compositional changes of AP-1 were associated with an elevation of c-Jun and JunB protein levels and the appearance of phosphorylated c-Jun and ATF-2 at 15-40 h posttreatment. Immunocytochemistry and staining with Hoechst 33258 revealed an accumulation of phosphorylated c-Jun protein in apoptotic cells. Because c-Jun expression and transcriptional activity are stimulated by phosphorylation at Ser63/73 by c-Jun N-terminal kinase (JNK), we measured JNK activities. We found prolonged induction of JNK activity in extracts from cyclosporin-treated cells, which suggests an involvement of persistent JNK activation in the initiation of glioma cell apoptosis. We provided evidence that variations in AP-1 composition and phosphorylation resulted in modification of trans-activating potential toward different promoters. Whereas collagenase AP-1/TRE-dependent transcription was down-regulated during apoptosis, Fas ligand promoter became activated.
Pyrzynska
B
B
Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
Mosieniak
G
G
Kaminska
B
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D016572:Cyclosporine / Q000494:pharmacology*; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018808:Transcription Factor AP-1; D016572:Cyclosporine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases