Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.
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18 June 2001
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June 11 2001
Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation
Valérie Lallemand-Breitenbach,
Valérie Lallemand-Breitenbach
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Jun Zhu,
Jun Zhu
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Francine Puvion,
Francine Puvion
bCNRS UPR 9044, BP 8 Institut de Recherche sur le Cancer, 94801 Villejuif, France
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Marcel Koken,
Marcel Koken
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Nicole Honoré,
Nicole Honoré
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Alexandre Doubeikovsky,
Alexandre Doubeikovsky
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Estelle Duprez,
Estelle Duprez
cMolecular Structure and Function Laboratory, Imperial Cancer Research Fund, WC2A3PX London, United Kingdom
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Pier Paolo Pandolfi,
Pier Paolo Pandolfi
dDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021
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Edmond Puvion,
Edmond Puvion
bCNRS UPR 9044, BP 8 Institut de Recherche sur le Cancer, 94801 Villejuif, France
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Paul Freemont,
Paul Freemont
cMolecular Structure and Function Laboratory, Imperial Cancer Research Fund, WC2A3PX London, United Kingdom
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Hugues de Thé
Hugues de Thé
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
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Valérie Lallemand-Breitenbach
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
Jun Zhu
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
Francine Puvion
bCNRS UPR 9044, BP 8 Institut de Recherche sur le Cancer, 94801 Villejuif, France
Marcel Koken
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
Nicole Honoré
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
Alexandre Doubeikovsky
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
Estelle Duprez
cMolecular Structure and Function Laboratory, Imperial Cancer Research Fund, WC2A3PX London, United Kingdom
Pier Paolo Pandolfi
dDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021
Edmond Puvion
bCNRS UPR 9044, BP 8 Institut de Recherche sur le Cancer, 94801 Villejuif, France
Paul Freemont
cMolecular Structure and Function Laboratory, Imperial Cancer Research Fund, WC2A3PX London, United Kingdom
Hugues de Thé
aCentre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N°11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Affilié à l'Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France
V. Lallemand-Breitenbach and J. Zhu contributed equally to this work.
This work was presented at the Cold Spring Harbor meeting on “Dynamic Organization of Nuclear Function” on September 13–17, 2000.
Abbreviations used in this paper: APL, acute promyelocytic leukemia; CHO, Chinese hamster ovary; HA, hemagglutinin; LMB, leptomycin B; MEF, mouse embryo fibroblast; NB, nuclear body; NLS, nuclear localization signal; PML, promyelocytic leukemia; RA, retinoic acid; RAR, RA receptor; RBCC, RING-B-box-coiled-coil.
Received:
February 12 2001
Revision Requested:
April 19 2001
Accepted:
May 08 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2001 The Rockefeller University Press
2001
The Rockefeller University Press
J Exp Med (2001) 193 (12): 1361–1372.
Article history
Received:
February 12 2001
Revision Requested:
April 19 2001
Accepted:
May 08 2001
Citation
Valérie Lallemand-Breitenbach, Jun Zhu, Francine Puvion, Marcel Koken, Nicole Honoré, Alexandre Doubeikovsky, Estelle Duprez, Pier Paolo Pandolfi, Edmond Puvion, Paul Freemont, Hugues de Thé; Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation. J Exp Med 18 June 2001; 193 (12): 1361–1372. doi: https://doi.org/10.1084/jem.193.12.1361
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