title: Ultraviolet radiation-induced apoptosis is mediated by Daxx.
abstract: UV irradiation and other stress-activated signals activate the Jun N-terminal kinase (JNK, SAPK) pathway. The induction of JNK activity results in the activation of proto-oncogene c-Jun and activator protein-1 (AP-1) transcriptional activity. Data presented here show that UV mediated the activation of JNK correlated with UV-induced apoptosis and that overexpression of a dominant negative JNK blocked UV-induced apoptosis. However, the molecular events that lead to JNK activation in response to UV treatment are not clear. In this report, we provide evidence that a Fas receptor binding protein, Daxx, mediates UV-induced JNK activation and apoptosis. A dominant negative Daxx, coding for the C-terminal region (112 amino acids) of Daxx, was constructed and used in the experiments. Our data show that overexpression of the dominant negative Daxx partially inhibits UV-induced JNK phosphorylation in 293 cells. Inhibition of JNK phosphorylation resulted in the inhibition of c-Jun activation upon UV irradiation. Our data also show that the inhibition of JNK activation by dominant negative Daxx correlates with the reduced rate of apoptotic death of 293 cells after UV irradiation. Surprisingly, overexpression of wild-type Daxx also inhibited UV-induced apoptosis, suggesting that Daxx competes for Fas receptor binding sites with other proapoptotic factors such as FADD. In addition, overexpression of a dominant negative mutant of FADD did not affect UV-induced JNK activation but does inhibit UV-induced apoptosis. These results suggest that UV-induced JNK activation is not sufficient but required for induction of apoptosis.
authors.affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
authors.forename: Heather N
authors.initials: HN
authors.lastname: Loke
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000528:radiation effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000378:metabolism / Q000528:radiation effects; D008164:Luminescent Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones; D016296:Mutagenesis / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D017931:DNA Primers; D029968:Escherichia coli Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; C000715470:MAS1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003066:Coenzyme A Ligases; C085934:acyl-coenzyme A synthetase, E coli