1: Chem Biol Interact. 2005 May 30;153-154:171-8. Epub 2005 Apr 18. 

The role of c-MYB in benzene-initiated toxicity.

Wan J, Badham HJ, Winn L.

Department of Pharmacology and Toxicology and School of Environmental Studies,
Queen's University, Botterell Hall Room 557, Kingston, Ont., Canada K7L 3N6.

Chronic exposure to benzene has been correlated with increased oxidative stress
and leukemia. Oncogene activation, including c-Myb activation, is one of the
earliest steps leading to the formation of leukemic cells, however the molecular
mechanisms involved in these events are poorly understood. Given that oxidative
stress can alter the activity and fate of cell signaling pathways we hypothesize
that the bioactivation of benzene leads to the formation of reactive oxygen
species (ROS), which if not detoxified can alter the c-Myb signaling pathway.
Using chicken erythroblast HD3 cells we have shown that exposure to the benzene
metabolites catechol, benzoquinone, and hydroquinone leads to increased c-Myb
activity, increased phosphorylation of c-Myb and increased production of ROS
supporting our hypothesis. Activation of the aryl hydrocarbon receptor (AhR) by
environmental contaminants has also been associated with carcinogenesis and mice
lacking this receptor are resistant to benzene-initiated hematotoxicity. Using
wild type and AhR deficient cells we are investigating the role of this receptor
in benzene-initiated alterations in the c-Myb signaling pathway. We have found
that both wild type and AhR deficient cells are sensitive to catechol and
hydroquinone-initiated increases in c-Myb activity while both cell types are
resistant to benzene-initiated alterations leaving the role of the AhR still
undetermined. Interestingly, protein expression of c-Myb is increased after
catechol exposure in AhR deficient cells while decreased in wild-type cells.
Further studies on the role of the AhR in benzene-initiated alterations on the
c-Myb signaling pathway are on going.

Publication Types:
    Review
    Review, Tutorial

PMID: 15935814 [PubMed - indexed for MEDLINE]


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2: J Biol Chem. 2002 Jun 21;277(25):22515-9. Epub 2002 Apr 15. 

Myb-binding protein 1a augments AhR-dependent gene expression.

Jones LC, Okino ST, Gonda TJ, Whitlock JP Jr.

Division of Hematology and Oncology, Cedars Sinai Medical Center, UCLA School of
Medicine, Los Angeles, California 90048, USA.

We have studied the mechanism by which an acidic domain (amino acids 515-583) of
the aromatic hydrocarbon receptor (AhR) transactivates a target gene. Studies
with glutathione S-transferase fusion proteins demonstrate that the wild-type
acidic domain associates in vitro with Myb-binding protein 1a, whereas a mutant
domain (F542A, I569A) does not. AhR-defective cells reconstituted with an AhR
containing the wild-type acidic domain exhibit normal AhR function; however,
cells reconstituted with an AhR containing the mutant acidic domain do not
function normally. Transient transfection of Myb-binding protein 1a into mouse
hepatoma cells is associated with augmentation of AhR-dependent gene expression.
Such augmentation does not occur when Myb-binding protein 1a is transfected into
AhR-defective cells that have been reconstituted with an AhR that lacks the
acidic domain. We infer that 1) Myb-binding protein 1a associates with AhR,
thereby enhancing transactivation, and 2) the presence of AhR's acidic domain is
both necessary and sufficient for Myb-binding protein 1a to increase
AhR-dependent gene expression.

PMID: 11956195 [PubMed - indexed for MEDLINE]


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