Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis.
The promyelocytic leukemia protein (PML) gene of acute promyelocytic leukemia (APL) encodes a cell growth and tumor suppressor essential for multiple apoptotic signals. Daxx was identified as a molecule important for the cytoplasmic transduction of the Fas proapoptotic stimulus. Here, we show that upon mitogenic activation of mature splenic lymphocytes, Daxx is dramatically upregulated and accumulates in the PML nuclear body (NB) where PML and Daxx physically interact. In the absence of PML, Daxx acquires a dispersed nuclear pattern, and activation-induced cell death of splenocytes is profoundly impaired. PML inactivation results in the complete abrogation of the Daxx proapoptotic ability. In APL cells, Daxx is delocalized from the NB. Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs. These results indicate that PML and Daxx cooperate in a novel NB-dependent pathway for apoptosis and shed new light in the role of PML in tumor suppression.
Zhong
S
S
Department of Human Genetics and the Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
Salomoni
P
P
Ronchetti
S
S
Guo
A
A
Ruggero
D
D
Pandolfi
P P
PP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000502:physiology* / Q000648:ultrastructure; D056970:Co-Repressor Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013737:Testis / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D011994:Recombinant Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins