The Journal of Experimental Medicine
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Published online 18 June 2001.
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© The Rockefeller University Press, 0022-1007/2001/6/1361/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 12, June 18, 2001 1361-1372

Original Article

Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor {alpha} Degradation

Valérie Lallemand-Breitenbacha, Jun Zhua, Francine Puvionb, Marcel Kokena, Nicole Honoréa, Alexandre Doubeikovskya, Estelle Duprezc, Pier Paolo Pandolfid, Edmond Puvionb, Paul Freemontc, and Hugues de Théa

a Centre 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
b CNRS UPR 9044, BP 8 Institut de Recherche sur le Cancer, 94801 Villejuif, France
c Molecular Structure and Function Laboratory, Imperial Cancer Research Fund, WC2A3PX London, United Kingdom
d Department of Human Genetics and Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021
CNRS UPR 9051, Hôpital St. Louis 1, Av. C. Vellefaux, 75475 Paris Cedex 10, France.33-1-53-7221-9033-1-53-7221-91

dethe{at}chu-stlouis.fr

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) {alpha} 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/RAR{alpha} 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/RAR{alpha} 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.

Key Words: leukemia • interferon • ubiquitin • nuclear matrix • arsenic

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.

© 2001 The Rockefeller University Press


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