A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D.
Cancer Res
; 72(4): 958-68, 2012 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-22207345
ABSTRACT
Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Vitamina D
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Proteínas Serina-Treonina Quinases
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Receptores de Calcitriol
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Proteínas de Ciclo Celular
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Transportadores de Cassetes de Ligação de ATP
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Receptor Cross-Talk
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Proteínas Supressoras de Tumor
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Proteínas de Ligação a DNA
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Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article