Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs).
Daxx was first identified as a protein that binds the cytosolic domain of Fas and links this receptor to an apoptosis pathway involving activation of Jun N-terminal kinase (JNK). We show here that cells overexpressing the human homolog of Daxx (hDaxx) display enhanced sensitivity to apoptosis induced by Fas but not by several other cell death stimuli. hDaxx-mediated enhancement of Fas-induced apoptosis was correlated with accelerated activation of caspases but not with JNK induction. Although specifically enhancing Fas function, hDaxx does not bind Fas and instead is found in the nucleus where it localizes to PML oncogenic domains (PODs). Moreover, the hDaxx protein also exhibits the ability to repress transcription. Mutagenesis studies demonstrated a correlation between the localization of hDaxx to PODs and its ability to enhance Fas-induced cell death. Arsenic trioxide (As(2)O(3)), an agent that accentuates POD formation, collaborated synergistically with overexpression of hDaxx to increase cellular sensitivity to Fas-induced apoptosis. Taken together, these findings argue that hDaxx promotes sensitivity to Fas from a nuclear location, probably by modulating the transcription of genes involved in Fas-induced caspase activation and apoptosis.
Torii
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S
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Egan
D A
DA
Evans
R A
RA
Reed
J C
JC
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D056970:Co-Repressor Proteins; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D011233:Precipitin Tests; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins; D015003:Yeasts; D019014:fas Receptor / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C070576:PML protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide