小鼠雙微癌基因（mdm2）是腫瘤抑制因子p53的一種重要負調控因子。為了闡明Mdm2分子上一個重要絲氨酸位點的磷酸化所發(fā)揮的調節(jié)功能,，Gannon等人構建了Mdm2絲氨酸位點突變型小鼠模型,。5月14日國際腫瘤學著名雜志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ATM激酶，進而穩(wěn)定和激活p53蛋白。盡管ATM引發(fā)的p53磷酸化在體內已被證實調節(jié)p53的水平和轉錄活性,，但這似乎并非p53穩(wěn)定性的主要調節(jié)者。
利用Mdm2突變型轉基因小鼠模型,，研究者首次證實,，在DNA損傷時，ATM對Mdm2第394位絲氨酸位點的磷酸化對于p53的穩(wěn)定和活化是至關重要的,。此外,，他們還發(fā)現(xiàn)Mdm2第394位絲氨酸位點的去磷酸化可下調p53介導的DNA損傷反應。從而進一步證實,，Mdm2第394位絲氨酸位點的磷酸化狀態(tài)掌控著DNA損傷時p53蛋白的水平和功能,。（生物谷Bioon.com）
doi:10.1016/j.ccr.2012.04.011
PMC:
PMID:
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.
