A Positive Feedback Signaling Loop between ATM and the Vitamin D Receptor Is Critical for Cancer Chemoprevention by Vitamin D

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

来源：Cancer Research, 2012, 72(4): 958-968.

DOI：10.1158/0008-5472.CAN-11-0042

Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1 alpha,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. Cancer Res; 72(4); 958-68.

• 出版日期2012-2-15
• 单位中国医科大学