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2088511 
Journal Article 
Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite 
Hirano, S; Watanabe, T; Kobayashi, Y 
In Press 
Yes 
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333 
273 
590-599 
English 
Inorganic arsenite (iAs(3+)) is a two-edged sword. iAs(3+) is a well-known human carcinogen; nevertheless, it has been used as a therapeutic drug for acute promyelocytic leukemia (APL), which is caused by a fusion protein comprising retinoic acid receptor-α and promyelocytic leukemia (PML). PML, a nuclear transcription factor, has a RING finger domain with densely positioned cysteine residues. To examine PML-modulated cellular responses to iAs(3+), CHO-K1 and HEK293 cells were each used to establish cell lines that expressed ectopic human PML. Overexpression of PML increased susceptibility to iAs(3+) in CHO-K1 cells, but not in HEK293 cells. Exposure of PML-transfected cells to iAs(3+) caused PML to change from a soluble form to less soluble forms, and this modification of PML was observable even with just 0.1μM iAs(3+) (7.5ppb). Western blot and immunofluorescent microscopic analyses revealed that the biochemical changes of PML were caused at least in part by conjugation with small ubiquitin-like modifier proteins (SUMOylation). A luciferase reporter gene was used to investigate whether modification of PML was caused by oxidative stress or activation of antioxidant response element (ARE) in CHO-K1 cells. Modification of PML protein occurred faster than activation of the ARE in response to iAs(3+), suggesting that PML was not modified as a consequence of oxidative stress-induced ARE activation. 
Arsenic; Promyelocytic leukemia; SUMO; Western blot; Oxidative stress; ICP-MS 
IRIS
• Arsenic Hazard ID
          PubMed
          Considered New
          PubMed
          ToxNet
          Considered New
          WOS
          WOS
          Excluded
               WOS Duplicates
     2. Lit Search Updates through Oct 2015
          PubMed
          WOS
          ToxNet
          Considered
     7. Other Studies through Oct 2015
          MOA
• Arsenic (Inorganic)
     1. Literature
          Lit search updates through Oct 2015
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
          Relevant
     5. Susceptibility Screening
          Excluded/Not relevant
• Arsenic MOA
     4. Adverse Outcome Pathways
          Gene expression changes
     1. MOA Literature Screening
          Health Effect Screening
          Susceptibility Screening
• Arsenic Susceptibility
     5. Health Effect
          Hematology, Hematopoietic System
     1. Susceptibility Literature Screening
          Keyword Search
     2. Excluded
          MOA/Mechanistic
     3. References Identified During Review