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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 
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333 
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 
• Arsenic Hazard ID
          Considered New
          Considered New
               WOS Duplicates
     2. Lit Search Updates through Oct 2015
     7. Other Studies through Oct 2015
• Arsenic (Inorganic)
     1. Literature
          Lit search updates through Oct 2015
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
     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
     3. References Identified During Review