A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D.
A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D.
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DOI：
10.1158/0008-5472.can-11-0042
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发表时间：
2012-02-15
期刊：
影响因子：
11.2
通讯作者：
Lee YF
中科院分区：
文献类型：
--
作者：
Ting HJ;Yasmin-Karim S;Yan SJ;Hsu JW;Lin TH;Zeng W;Messing J;Sheu TJ;Bao BY;Li WX;Messing E;Lee YF
流行病学和实验室研究均表明1α，25-二羟维生素D3（1，25-VD）在肿瘤发生中具有化学预防作用。然而，对1，25-VD预防肿瘤发生的分子机制的理解仍然不完全。在这项研究中，我们使用了一个建立的小鼠模型的化学致癌研究如何1，25-VD防止恶性转化。在这个模型中，1，25-VD促进了DNA修复基因RAD 50和ATM的表达，这两个基因对于介导DNA损伤的信号反应至关重要。相应地，1，25-VD通过促进双链断裂DNA修复保护细胞免受遗传毒性应激和生长抑制。维生素D受体（VDR）的耗竭降低了这些基因保护作用，并导致了1，25-VD无法预防的恶性转化，这定义了VDR在介导1，25-VD抗癌作用中的重要作用。值得注意的是，遗传毒性应激通过VDR的磷酸化激活ATM和VDR。在推定的ATM磷酸化位点的VDR突变损害了ATM增强VDR反式激活活性的能力，减少了1，25-VD介导的ATM和RAD 50表达的诱导。总之，我们的研究结果确定了一种新的维生素D介导的化学预防机制，涉及DNA修复蛋白ATM和VDR之间的正反馈回路。
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.