生物谷報道：美國哈佛醫(yī)學(xué)院的科學(xué)家在新一期的Molecular Cell上發(fā)表了一項關(guān)于p53脈沖發(fā)生的機制研究結(jié)果。p53是一種重要的腫瘤抑制蛋白,，是人類腫瘤細胞中通常失活的蛋白質(zhì)之一,。在DNA遭受損傷時，細胞內(nèi)p53濃度會呈現(xiàn)脈沖型變化,，其振幅和周期固定,。
p53蛋白質(zhì)能夠激活Mdm2轉(zhuǎn)錄，而Mdm2又能夠反過來促進p53蛋白的泛素化和降解，以往研究推測,，這一反饋調(diào)節(jié)模式能夠引起p53在細胞內(nèi)的脈沖型變化,。但是在細胞內(nèi)p53的濃度也受到其上游調(diào)節(jié)蛋白毛細血管擴張性共濟失調(diào)癥突變蛋白（ATM）和檢測點激酶（Chk2）的調(diào)控，其中ATM是將DNA損傷的信息傳遞給p53的感應(yīng)蛋白,。
Batchelor等研究人員用免疫印跡,、免疫熒光和視頻時差顯微等技術(shù)監(jiān)測細胞內(nèi)p53信號途徑中幾種重要蛋白質(zhì)的動態(tài)。結(jié)果發(fā)現(xiàn),，受γ射線損傷時細胞內(nèi)ATM和Chk2也表現(xiàn)出脈沖型變化,，且細胞內(nèi)p53脈沖是由ATM和Chk2的脈沖變化引起，p53和Mdm2之間的反饋調(diào)節(jié)并不足以產(chǎn)生多次自發(fā)的p53脈沖,。用RNA干擾的方法抑制p53在細胞內(nèi)的表達能夠增加Chk2的水平,，表明p53能夠反饋抑制其上游調(diào)節(jié)蛋白。通過進一步對p53調(diào)控網(wǎng)絡(luò)進行模型模擬和實驗驗證,，研究人員發(fā)現(xiàn),，受p53調(diào)節(jié)的一個下游蛋白質(zhì)磷酸酶Wip1能夠抑制ATM和Chk2的水平，此機制能夠控制γ輻射下p53脈沖的形狀和一致性等特征,。
研究人員推測,，持續(xù)的DNA損傷能夠反復(fù)激活A(yù)TM，并從而誘發(fā)p53脈沖,，ATM和p53的脈沖型變化可能允許細胞重新評測DNA損傷是否存在,。
已有其它研究表明，p53脈沖與細胞內(nèi)的基因表達調(diào)控和癌癥發(fā)生密切相關(guān),，因此通過Wip1或其它蛋白質(zhì)控制p53脈沖的振幅和周期將具有重要價值,。（生物谷www.bioon.com）
生物谷推薦原始出處：
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
[email protected]
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.
