The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX

Ye, RQ, Goodarzi, AA, Kurz, EU, Saito, S, Higashimoto, Y, Lavin, MF, Appella, E, Anderson, CW and Lees-Miller, SP (2004) The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX. Dna Repair, 3 3: 235-244. doi:10.1016/j.dnarep.2003.10.014


Author Ye, RQ
Goodarzi, AA
Kurz, EU
Saito, S
Higashimoto, Y
Lavin, MF
Appella, E
Anderson, CW
Lees-Miller, SP
Title The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX
Journal name Dna Repair   Check publisher's open access policy
ISSN 1568-7864
Publication date 2004-01-01
Sub-type Article (original research)
DOI 10.1016/j.dnarep.2003.10.014
Volume 3
Issue 3
Start page 235
End page 244
Total pages 10
Editor E. C. Friedberg
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Collection year 2004
Language eng
Subject C1
321204 Mental Health
730204 Child health
Abstract The ataxia-telangiectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR) and activates downstream DNA-damage signaling pathways. Although the role of ATM in the cellular response to ionizing radiation has been well characterized, its role in response to other DNA-damaging agents is less well defined. We previously showed that genistein, a naturally occurring isoflavonoid, induced increased ATM protein kinase activity, ATM-dependent phosphorylation of p53 on serine 15 and activation of the DNA-binding properties of p53. Here. we show that genistein also induces phosphorylation of p53 at serines 6, 9, 20,46, and 392, and that genistein-induced accumulation and phosphorylation of p53 is reduced in two ATM-deficient human cell lines. Also, we show that genistein induces phosphorylation of ATM on serine 1981 and phosphorylation of histone H2AX on serine 139. The related bioflavonoids, daidzein and biochanin A, did not induce either phosphorylation of p53 or ATM at these sites. Like genistein, quercetin induced phosphorylation of ATM on serine 198 1, and ATM-dependent phosphorylation of histone H2AX on serine 139; however, p53 accumulation and phosphorylation on serines 6, 9, 15, 20, 46, and 392 occurred in ATM-deficient cells, indicating that ATM is not required for quercetin-induced phosphorylation of p53. Our data suggest that genistein and quercetin induce different DNA-damage induced signaling pathways that, in the case of genistein, are highly ATM-dependent but, in the case of quercetin, may be ATM-dependent only for some downstream targets. (C) 2003 Elsevier B.V. All rights reserved.
Keyword Genetics & Heredity
Toxicology
P53
Genistein
Quercetin
Isoflavonoid
Dna Damage
Phosphorylation
Double-strand Breaks
Human-melanoma Cells
Ataxia-telangiectasia
Protein-kinase
Dna-damage
Posttranslational Modifications
Ionizing-radiation
Cancer Cells
In-vitro
Flavonoids
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2005 Higher Education Research Data Collection
School of Medicine Publications
 
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