Publication Date:
2010-04-10
Description:
Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xiao-Wei -- Yan, Xiao-Jing -- Zhou, Zi-Ren -- Yang, Fei-Fei -- Wu, Zi-Yu -- Sun, Hong-Bin -- Liang, Wen-Xue -- Song, Ai-Xin -- Lallemand-Breitenbach, Valerie -- Jeanne, Marion -- Zhang, Qun-Ye -- Yang, Huai-Yu -- Huang, Qiu-Hua -- Zhou, Guang-Biao -- Tong, Jian-Hua -- Zhang, Yan -- Wu, Ji-Hui -- Hu, Hong-Yu -- de The, Hugues -- Chen, Sai-Juan -- Chen, Zhu -- New York, N.Y. -- Science. 2010 Apr 9;328(5975):240-3. doi: 10.1126/science.1183424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20378816" target="_blank"〉PubMed〈/a〉
Keywords:
Arsenic/*metabolism
;
Arsenicals/*metabolism/*pharmacology
;
Cell Line
;
Humans
;
Leukemia, Promyelocytic, Acute/drug therapy/genetics
;
Mutant Proteins/chemistry/metabolism
;
Mutation
;
Nuclear Proteins/chemistry/genetics/*metabolism
;
Oncogene Proteins, Fusion/chemistry/genetics/*metabolism
;
Oxazines/metabolism
;
Oxides/*metabolism/*pharmacology
;
Protein Conformation
;
Protein Multimerization
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Receptors, Retinoic Acid/metabolism
;
Recombinant Fusion Proteins/chemistry/metabolism
;
Small Ubiquitin-Related Modifier Proteins/metabolism
;
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
;
Transcription Factors/chemistry/genetics/*metabolism
;
Tumor Suppressor Proteins/chemistry/genetics/*metabolism
;
Ubiquitination
;
Zinc Fingers
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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