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PMID: 11413191 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation.

The Journal of experimental medicine ·Vol. 193 ·No. 12 ·2001-06-18 ·Pages 1361-71

Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de Thé H

Abstract

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/RARalpha 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/RARalpha 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.

MeSH Terms
Adenosine Triphosphatases/metabolism Amino Acid Motifs Animals Arsenic Trioxide Arsenicals/pharmacology CHO Cells Cell Line Cell Nucleus/metabolism Cells, Cultured Cricetinae Endopeptidases Mice Models, Biological Mutation Neoplasm Proteins/chemistry,genetics,metabolism Nuclear Matrix/metabolism Nuclear Proteins Oxides/pharmacology Promyelocytic Leukemia Protein Proteasome Endopeptidase Complex Protein Isoforms/chemistry Protein Transport Receptors, Retinoic Acid/metabolism Retinoic Acid Receptor alpha SUMO-1 Protein Transcription Factors/chemistry,genetics,metabolism Tumor Suppressor Proteins Ubiquitins/metabolism
Chemicals
Arsenicals Neoplasm Proteins Nuclear Proteins Oxides Pml protein, mouse Promyelocytic Leukemia Protein Protein Isoforms Rara protein, mouse Receptors, Retinoic Acid Retinoic Acid Receptor alpha SUMO-1 Protein Transcription Factors Tumor Suppressor Proteins Ubiquitins Endopeptidases Proteasome Endopeptidase Complex 26S proteasome non-ATPase regulatory subunit 13 Adenosine Triphosphatases Arsenic Trioxide
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lallemand-Breitenbach V
Centre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N degrees 11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France.
Zhu J
Puvion F
Koken M
Honoré N
Doubeikovsky A
Duprez E
Pandolfi P P
Puvion E
Freemont P
de Thé H
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.193.12.1361
Published
2001-06-18
Pages
1361-71
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193303
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.193.12.1361 PMC Full Text View journal details
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