In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 4 ( 2012-02-15), p. 958-968
Abstract:
Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D3 (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. Cancer Res; 72(4); 958–68. ©2011 AACR.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-11-0042
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3