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Tags
HERO ID
2088511
Reference Type
Journal Article
Title
Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite
Author(s)
Hirano, S; Watanabe, T; Kobayashi, Y
Year
2013
Is Peer Reviewed?
1
Journal
Toxicology and Applied Pharmacology
ISSN:
0041-008X
EISSN:
1096-0333
Volume
273
Issue
3
Page Numbers
590-599
Language
English
PMID
24135626
DOI
10.1016/j.taap.2013.10.004
Web of Science Id
WOS:000328711700019
Abstract
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.
Keywords
Arsenic; Promyelocytic leukemia; SUMO; Western blot; Oxidative stress; ICP-MS
Tags
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
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