生物谷报道：美国哈佛医学院的科学家在新一期的Molecular Cell上发表了一项关于p53脉冲发生的机制研究结果。p53是一种重要的肿瘤抑制蛋白，是人类肿瘤细胞中通常失活的蛋白质之一。在DNA遭受损伤时，细胞内p53浓度会呈现脉冲型变化，其振幅和周期固定。
p53蛋白质能够激活Mdm2转录，而Mdm2又能够反过来促进p53蛋白的泛素化和降解，以往研究推测，这一反馈调节模式能够引起p53在细胞内的脉冲型变化。但是在细胞内p53的浓度也受到其上游调节蛋白毛细血管扩张性共济失调症突变蛋白（ATM）和检测点激酶（Chk2）的调控，其中ATM是将DNA损伤的信息传递给p53的感应蛋白。
Batchelor等研究人员用免疫印迹、免疫荧光和视频时差显微等技术监测细胞内p53信号途径中几种重要蛋白质的动态。结果发现，受γ射线损伤时细胞内ATM和Chk2也表现出脉冲型变化，且细胞内p53脉冲是由ATM和Chk2的脉冲变化引起，p53和Mdm2之间的反馈调节并不足以产生多次自发的p53脉冲。用RNA干扰的方法抑制p53在细胞内的表达能够增加Chk2的水平，表明p53能够反馈抑制其上游调节蛋白。通过进一步对p53调控网络进行模型模拟和实验验证，研究人员发现，受p53调节的一个下游蛋白质磷酸酶Wip1能够抑制ATM和Chk2的水平，此机制能够控制γ辐射下p53脉冲的形状和一致性等特征。
研究人员推测，持续的DNA损伤能够反复激活ATM，并从而诱发p53脉冲，ATM和p53的脉冲型变化可能允许细胞重新评测DNA损伤是否存在。
已有其它研究表明，p53脉冲与细胞内的基因表达调控和癌症发生密切相关，因此通过Wip1或其它蛋白质控制p53脉冲的振幅和周期将具有重要价值。（生物谷www.bioon.com）
生物谷推荐原始出处：
Molecular Cell，Vol 30, 277-289, 09 May 2008，Eric Batchelor, Galit Lahav
Recurrent Initiation: A Mechanism for Triggering p53 Pulses in Response to DNA Damage
Eric Batchelor,1 Caroline S. Mock,1 Irun Bhan,1,2 Alexander Loewer,1 and Galit Lahav1,
1 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
2 Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, MA 02115, USA
Corresponding author
Galit Lahav
galit@hms.harvard.edu
Summary
DNA damage initiates a series of p53 pulses. Although much is known about the interactions surrounding p53, little is known about which interactions contribute to p53's dynamical behavior. The simplest explanation is that these pulses are oscillations intrinsic to the p53/Mdm2 negative feedback loop. Here we present evidence that this simple mechanism is insufficient to explain p53 pulses; we show that p53 pulses are externally driven by pulses in the upstream signaling kinases, ATM and Chk2, and that the negative feedback between p53 and ATM, via Wip1, is essential for maintaining the uniform shape of p53 pulses. We propose that p53 pulses result from repeated initiation by ATM, which is reactivated by persistent DNA damage. Our study emphasizes the importance of collecting quantitative dynamic information at high temporal resolution for understanding the regulation of signaling pathways and opens new ways to manipulate p53 pulses to ask questions about their function in response to DNA damage.
