小鼠雙微癌基因（mdm2）是腫瘤抑制因子p53的一種重要負(fù)調(diào)控因子,。為了闡明Mdm2分子上一個(gè)重要絲氨酸位點(diǎn)的磷酸化所發(fā)揮的調(diào)節(jié)功能，Gannon等人構(gòu)建了Mdm2絲氨酸位點(diǎn)突變型小鼠模型,。5月14日國際腫瘤學(xué)著名雜志Cancer Cell發(fā)表了該研究小組的研究論文“ATM Phosphorylation of Mdm2 Ser394 Regulates the Amplitude and Duration of the DNA Damage Response in Mice”,。
以往研究表明，電離輻射引起的DNA損傷可激活A(yù)TM激酶,，進(jìn)而穩(wěn)定和激活p53蛋白,。盡管ATM引發(fā)的p53磷酸化在體內(nèi)已被證實(shí)調(diào)節(jié)p53的水平和轉(zhuǎn)錄活性，但這似乎并非p53穩(wěn)定性的主要調(diào)節(jié)者,。
利用Mdm2突變型轉(zhuǎn)基因小鼠模型,，研究者首次證實(shí)，在DNA損傷時(shí),，ATM對(duì)Mdm2第394位絲氨酸位點(diǎn)的磷酸化對(duì)于p53的穩(wěn)定和活化是至關(guān)重要的,。此外，他們還發(fā)現(xiàn)Mdm2第394位絲氨酸位點(diǎn)的去磷酸化可下調(diào)p53介導(dǎo)的DNA損傷反應(yīng),。從而進(jìn)一步證實(shí),，Mdm2第394位絲氨酸位點(diǎn)的磷酸化狀態(tài)掌控著DNA損傷時(shí)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.
