The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor- and DNA-dependent kinase phosphorylation.
Radiother Oncol
; 84(3): 328-34, 2007 Sep.
Article
em En
| MEDLINE
| ID: mdl-17714814
ABSTRACT
BACKGROUND AND PURPOSE:
Purpose of the study was to elucidate the underlying molecular mechanism of the radioprotector O-phospho-tyrosine (P-Tyr).METHODS:
Molecular effects of P-Tyr at the level of EGFR responses were investigated in vitro with bronchial carcinoma cell line A549. Nuclear EGFR transport and DNA-PK activation were quantified after Western blotting. Residual DNA-damages were quantified by help of gammaH(2)AX focus assay.RESULTS:
As determined by dose-response curves, treatment of cells with P-Tyr for 16h before irradiation results in radioprotection. Simultaneous treatment with EGFR blocking antibody Cetuximab abolished P-Tyr associated radioprotection. At the molecular level P-Tyr mediated a general phosphorylation of EGFR and a pronounced phosphorylation of nuclear EGFR at residue Thr No. 654, also observed after treatment with ionizing radiation. This phosphorylation was associated with nuclear EGFR accumulation. Moreover, P-Tyr-triggered EGFR nuclear accumulation was associated with phosphorylation of DNA-PK at Thr 2609. This activated form of DNA-PK was not DNA associated, but after radiation, DNA binding increased, particularly after P-Tyr pre-treatment. These molecular effects of P-Tyr resulted in a reduction of residual DNA-damage after irradiation.CONCLUSIONS:
Radioprotection by P-Tyr is mediated through its stimulation of nuclear EGFR transport and concurrent, but DNA-damage independent, activation of DNA-PK. Thus, subsequent irradiation results in increased binding of DNA-PK to DNA, improved DNA-repair and increased cell survival.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Protetores contra Radiação
/
Fosfotirosina
/
Reparo do DNA
/
Proteína Quinase Ativada por DNA
/
Receptores ErbB
Limite:
Humans
Idioma:
En
Revista:
Radiother Oncol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Alemanha