Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite.

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 0.1 μM iAs(3+) (7.5 ppb). 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.

• Authors: Seishiro Hirano, Takayuki Watanabe, Yayoi Kobayashi
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 273 Issue 3 Pg. 590-9 (Dec 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 24135626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Antineoplastic Agents
• Arsenites
• Oncogene Proteins, Fusion
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• SUMO-1 Protein
• SUMO1 protein, human
• Transcription Factors
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• arsenite

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antioxidant Response Elements
• Arsenites (pharmacology)
• CHO Cells
• Cricetulus
• HEK293 Cells
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy, pathology)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Oxidative Stress (drug effects)
• Receptors, Retinoic Acid (genetics, metabolism)
• Retinoic Acid Receptor alpha
• SUMO-1 Protein (genetics, metabolism)
• Transcription Factors (genetics, metabolism)