DOI: 10.1084/jem.191.4.631. Promyelocytic Leukemia Protein (Pml) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis

Promyelocytic Leukemia Protein (Pml) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis

10.1084/jem.191.4.631

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

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.

Bibliography

Zhong, S., Salomoni, P., Ronchetti, S., Guo, A., Ruggero, D., & Pandolfi, P. P. (2000). Promyelocytic Leukemia Protein (Pml) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis. The Journal of Experimental Medicine, 191(4), 631â640.

Authors 6

Sue Zhong (first)
Paolo Salomoni (additional)
Simona Ronchetti (additional)
Ailan Guo (additional)
Davide Ruggero (additional)
Pier Paolo Pandolfi (additional)

References 24 Referenced 192

{'key': '2023072509063450600_R1', 'first-page': '1285', 'article-title': 'Structure and origin of the acute promyelocytic leukemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties', 'volume': '6', 'author': 'Pandolfi', 'year': '1991', 'journal-title': 'Oncogene.'} / Oncogene. / Structure and origin of the acute promyelocytic leukemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties by Pandolfi (1991)
10.1016/0092-8674(91)90113-D / Cell. / The PML/RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR by de Thé (1991)
10.1016/0092-8674(91)90112-C / Cell. / Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML by Kakizuka (1991)
10.1126/science.1720570 / Science. / Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia by Goddard (1991)
10.1038/sj.onc.1203088 / Oncogene. / In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications by He (1999)
10.1182/blood.V93.10.3167.410k44_3167_3215 / Blood. / Deconstructing a diseaseRARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia by Melnick (1999)
10.1016/0092-8674(91)90229-R / Cell. / A novel cysteine-rich sequence motif by Freemont (1991)
10.3109/10428199809050925 / Leuk. Lymphoma. / Acute promyelocytic leukemia as a model for cross-talk between interferon and retinoic acid pathwaysfrom molecular biology to clinical applications by Gaboli (1998)
10.1086/301991 / Am. J. Hum. Genet. / Structure, organization, and dynamics of promyelocytic leukemia protein nuclear bodies by Hodges (1998)
10.1126/science.279.5356.1547 / Science. / Role of PML in cell growth and the retinoic acid pathway by Wang (1998)
10.1038/3073 / Nat. Genet. / Pml is essential for multiple apoptotic pathways by Wang (1998)
10.1002/j.1460-2075.1994.tb06356.x / EMBO (Eur. Mol. Biol. Organ.) J. / The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion by Koken (1994)
10.1016/0092-8674(94)90340-9 / Cell. / A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein by Dyck (1994)
10.1016/0092-8674(94)90341-7 / Cell. / Retinoic acid regulates aberrant nuclear localization of PML-RARα in acute promyelocytic leukemic cells by Weis (1994)
10.1182/blood.V83.1.10.10 / Blood. / Acute promyelocytic leukemiafrom genetics to treatment by Grignani (1994)
10.1016/S0092-8674(00)80294-9 / Cell. / Daxx, a novel Fas-binding protein that activates JNK and apoptosis by Yang (1997)
10.1242/jcs.111.14.2029 / J. Cell Sci. / Interphase-specific association of intrinsic centromere protein CENP-C with HDaxx, a death domain-binding protein implicated in Fas-mediated cell death by Pluta (1998)
10.1101/gad.13.15.1918 / Genes Dev. / Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development by Michaelson (1999)
10.1126/science.281.5384.1860 / Science. / Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx by Chang (1998)
10.1073/pnas.96.4.1252 / Proc. Natl. Acad. Sci. USA. / Dissecting Fas signaling with an altered-specificity death-domain mutantrequirement of FADD binding for apoptosis but not Jun N-terminal kinase activation by Chang (1999)
{'key': '2023072509063450600_R21', 'first-page': '1164', 'article-title': 'Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation', 'volume': '10', 'author': 'Filvaroff', 'year': '1990', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Tyrosine phosphorylation is an early and specific event involved in primary keratinocyte differentiation by Filvaroff (1990)
10.1101/gad.10.22.2859 / Genes Dev. / BIDa novel BH3 domain-only death agonist by Wang (1996)
10.1038/15463 / Nat. Genet. / A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARα and T18 oncoproteins by Zhong (1999)
{'key': '2023072509063450600_R24', 'first-page': '1173', 'article-title': 'Distinct apoptotic responses in maturation sensitive and resistant t(15;17) acute promyelocytic leukemia NB4 cells. 9-cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression', 'volume': '9', 'author': 'Bruel', 'year': '1995', 'journal-title': 'Leukemia.'} / Leukemia. / Distinct apoptotic responses in maturation sensitive and resistant t(15;17) acute promyelocytic leukemia NB4 cells. 9-cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression by Bruel (1995)

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:48 p.m.)
Deposited	2 years, 1 month ago (July 25, 2023, 6:18 a.m.)
Indexed	4 weeks, 2 days ago (Aug. 2, 2025, 1:04 a.m.)
Issued	25 years, 6 months ago (Feb. 21, 2000)
Published	25 years, 6 months ago (Feb. 21, 2000)
Published Online	25 years, 6 months ago (Feb. 21, 2000)
Published Print	25 years, 6 months ago (Feb. 21, 2000)

Funders 0

None

BibTeX

@article{Zhong_2000, title={Promyelocytic Leukemia Protein (Pml) and Daxx Participate in a Novel Nuclear Pathway for Apoptosis}, volume={191}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.191.4.631}, DOI={10.1084/jem.191.4.631}, number={4}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Zhong, Sue and Salomoni, Paolo and Ronchetti, Simona and Guo, Ailan and Ruggero, Davide and Pandolfi, Pier Paolo}, year={2000}, month=feb, pages={631–640} }

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      "author": "Goddard",
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      "article-title": "In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications",
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      "author": "He",
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      "author": "Melnick",
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