近日來(lái)自南京大學(xué)生物物理所的研究人員在最新一期的《美國(guó)科學(xué)院院刊》（PNAS）上發(fā)表了一篇題為“Two-phase dynamics of p53 in the DNA damage response”的研究論文,，解析了在DNA損傷反應(yīng)中p53的兩階段動(dòng)力學(xué)機(jī)制。
南京大學(xué)的生物物理所的王煒教授及劉鋒教授為這一文章的共同通訊作者,。王煒教授于1999年受聘為長(zhǎng)江計(jì)劃特聘教授,，現(xiàn)任南京大學(xué)生物物理所所長(zhǎng),。曾榮獲中國(guó)青年科技獎(jiǎng)和香港求是基金會(huì)杰出青年研究獎(jiǎng)，在國(guó)際重要學(xué)術(shù)雜志上發(fā)表學(xué)術(shù)論文150余篇,。劉鋒教授1998年12月于南京大學(xué)獲得理學(xué)博士學(xué)位,，1999年至今留任南京大學(xué)物理系工作，現(xiàn)為南京大學(xué)物理學(xué)教授,、博士生導(dǎo)師,。曾獲教育部“新世紀(jì)優(yōu)秀人才”稱號(hào)。
P53基因是迄今發(fā)現(xiàn)與人類腫瘤相關(guān)性最高的基因,，其編碼蛋白能與DNA特異結(jié)合,，活性受到磷酸化、乙?；?、甲基化、泛素化等翻譯后修飾調(diào)控,。正常P53蛋白的生物功能好似“基因組衛(wèi)士”,，在G1期檢查DNA損傷點(diǎn)，監(jiān)視基因組的完整性,。如有損傷,，P53蛋白阻止DNA復(fù)制，以提供足夠的使損傷DNA修復(fù),；如果修復(fù)失敗,，P53蛋白則引發(fā)細(xì)胞凋亡。近十年來(lái),，科學(xué)家們針對(duì)P53的功能,、調(diào)控機(jī)制及基因治療開(kāi)展了廣泛而深入的研究。然而科學(xué)家們對(duì)于p53在DNA損傷反應(yīng)中是誘導(dǎo)細(xì)胞周期阻滯/DNA修復(fù)或是誘導(dǎo)凋亡之間選擇的分子機(jī)制仍不是十分清楚,。
在這篇文章中,，研究人員構(gòu)建了一個(gè)p53信號(hào)網(wǎng)絡(luò)四單元模型，并將網(wǎng)絡(luò)動(dòng)態(tài)與電離輻射后的細(xì)胞反應(yīng)聯(lián)系起來(lái),。研究人員發(fā)現(xiàn)細(xì)胞反應(yīng)受到p53水平及翻譯后修飾的雙重調(diào)控,，且p53是以漸進(jìn)的方式逐步激活：首先p53通過(guò)初步的修飾Ser-15/20位點(diǎn)磷酸化部分激活誘導(dǎo)細(xì)胞周期阻滯，p53的水平呈現(xiàn)脈沖型變化,；在經(jīng)歷臨界值p53脈沖后如果DNA損傷仍無(wú)法修復(fù),，p53則會(huì)在隨后被另一種修飾即Ser-46位點(diǎn)磷酸化完全激活啟動(dòng)凋亡，此時(shí)p53濃度將轉(zhuǎn)換至相當(dāng)高的水平,。這表明p53在無(wú)法修復(fù)的損傷細(xì)胞中經(jīng)歷了兩階段反應(yīng),。p53的這種脈沖式及開(kāi)關(guān)樣的反應(yīng)代表了一種靈活、有效的控制模式，既避免了過(guò)早的凋亡,，又推動(dòng)了凋亡的執(zhí)行,。在這一模型中，研究人員還證實(shí)持續(xù)的DNA損傷能夠反復(fù)激活毛細(xì)血管擴(kuò)張性共濟(jì)失調(diào)癥突變蛋白（ATM）,，從而誘發(fā)p53脈沖,。p53-Mdm2和ATM-p53-Wip1負(fù)反饋環(huán)對(duì)p53在細(xì)胞內(nèi)的脈沖型變化起重要影響，而在p53-PTEN-Akt-Mdm2正反饋環(huán)發(fā)揮優(yōu)勢(shì)作用時(shí)p53則會(huì)發(fā)生功能轉(zhuǎn)換,。
新研究結(jié)果表明細(xì)胞有可能是通過(guò)不同反饋環(huán)的一系列主導(dǎo)作用啟動(dòng)了p53多個(gè)階段的動(dòng)態(tài)反應(yīng),。這一研究工作提供了關(guān)于p53動(dòng)力學(xué)及細(xì)胞命運(yùn)定向的新機(jī)制。（生物谷Bioon.com）
生物谷推薦原文：
Proceedings of the National Academy of Sciences DOI： 10.1073/pnas.1100600108
Two-phase dynamics of p53 in the DNA damage response
Zhang, Xiao-Peng; Liu, Feng; Wang, Wei
The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choosebetween these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associatedthe network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by boththe level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partiallyactivated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varyingin a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated byfurther modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather highlevels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-likebehaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the executionof apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNAdamage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavioroccurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominanceof distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamicsand cell fate decision.
