A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D

Huei Ju Ting, Sayeda Yasmin-Karim, Shian Jang Yan, Jong Wei Hsu, Tzu Hua Lin, Weisi Zeng, James Messing, Tzong Jeng Sheu, Bo Ying Bao, Willis X. Li, Edward Messing, Yi Fen Lee

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45 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)958-968
頁數11
期刊Cancer Research
72
發行號4
DOIs
出版狀態Published - 2012 2月 15

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究

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