小鼠双微癌基因（mdm2）是肿瘤抑制因子p53的一种重要负调控因子。为了阐明Mdm2分子上一个重要丝氨酸位点的磷酸化所发挥的调节功能，Gannon等人构建了Mdm2丝氨酸位点突变型小鼠模型。5月14日国际肿瘤学著名杂志Cancer Cell发表了该研究小组的研究论文“ATM Phosphorylation of Mdm2 Ser394 Regulates the Amplitude and Duration of the DNA Damage Response in Mice”。
以往研究表明，电离辐射引起的DNA损伤可激活ATM激酶，进而稳定和激活p53蛋白。尽管ATM引发的p53磷酸化在体内已被证实调节p53的水平和转录活性，但这似乎并非p53稳定性的主要调节者。
利用Mdm2突变型转基因小鼠模型，研究者首次证实，在DNA损伤时，ATM对Mdm2第394位丝氨酸位点的磷酸化对于p53的稳定和活化是至关重要的。此外，他们还发现Mdm2第394位丝氨酸位点的去磷酸化可下调p53介导的DNA损伤反应。从而进一步证实，Mdm2第394位丝氨酸位点的磷酸化状态掌控着DNA损伤时p53蛋白的水平和功能。（生物谷Bioon.com）
doi:10.1016/j.ccr.2012.04.011
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ATM Phosphorylation of Mdm2 Ser394 Regulates the Amplitude and Duration of the DNA Damage Response in Mice
Hugh S. Gannon1, Bruce A. Woda2 and Stephen N. Jones
DNA damage induced by ionizing radiation activates the ATM kinase, which subsequently stabilizes and activates the p53 tumor suppressor protein. Although phosphorylation of p53 by ATM was found previously to modulate p53 levels and transcriptional activities in vivo, it does not appear to be a major regulator of p53 stability. We have utilized mice bearing altered Mdm2 alleles to demonstrate that ATM phosphorylation of Mdm2 serine 394 is required for robust p53 stabilization and activation after DNA damage. In addition, we demonstrate that dephosphorylation of Mdm2 Ser394 regulates attenuation of the p53-mediated response to DNA damage. Therefore, the phosphorylation status of Mdm2 Ser394 governs p53 protein levels and functions in cells undergoing DNA damage.
