Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology*
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COS Cells
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Carrier Proteins / metabolism*
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Cell Nucleus / physiology*
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Cell Nucleus / ultrastructure
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Co-Repressor Proteins
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Intracellular Signaling Peptides and Proteins*
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Lymphocyte Activation
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Lymphocytes / cytology*
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Lymphocytes / physiology*
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Male
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Mice
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Mice, Knockout
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Molecular Chaperones
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / metabolism
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Promyelocytic Leukemia Protein
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Recombinant Proteins / metabolism
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Signal Transduction
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Spleen / immunology
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Testis / metabolism
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Tumor Suppressor Proteins
Substances
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Carrier Proteins
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Co-Repressor Proteins
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Daxx protein, mouse
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Intracellular Signaling Peptides and Proteins
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Molecular Chaperones
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Neoplasm Proteins
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Nuclear Proteins
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Recombinant Proteins
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Transcription Factors
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Tumor Suppressor Proteins