世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（三十三）

（11.22 -- 11.28 / 2010）
美寶國(guó)際集團(tuán):陶國(guó)新 

　　本周動(dòng)態(tài)包括以下內(nèi)容：生長(zhǎng)因子TGF-β2和BMP4可使成熟細(xì)胞轉(zhuǎn)化為成人干細(xì)胞；脂肪組織可生成免疫細(xì)胞；預(yù)設(shè)基因線路可指示人體細(xì)胞按需分化；無(wú)需動(dòng)物實(shí)驗(yàn)即可快速篩選抗癌藥物；恢復(fù)p53功能為主的腫瘤療法的局限性；蛋白酶體助生殖細(xì)胞“返老還童”  。

1. 生長(zhǎng)因子TGF-β2和BMP4可使成熟細(xì)胞轉(zhuǎn)化為成人干細(xì)胞
【摘要】
　　據(jù)美國(guó)物理學(xué)家組織網(wǎng)11月21日?qǐng)?bào)道，哈佛醫(yī)學(xué)院和哈佛牙科學(xué)院的研究人員在11月21日出版的《自然—醫(yī)學(xué)》雜志上撰文指出，通過(guò)模擬一種罕見(jiàn)的遺傳疾病，他們能夠讓成熟細(xì)胞回到成人干細(xì)胞狀態(tài)，新獲得的這種干細(xì)胞能分化成各種不同類型的細(xì)胞，在培養(yǎng)皿和動(dòng)物身上進(jìn)行的試驗(yàn)都獲得了成功。哈佛醫(yī)學(xué)院的細(xì)胞生物學(xué)家、哈佛牙科學(xué)院院長(zhǎng)布約恩·奧爾森表示，新發(fā)現(xiàn)在個(gè)性化醫(yī)療和組織工程學(xué)領(lǐng)域具有重要意義。進(jìn)行性骨化性纖維增殖不良癥（FOP）是一種罕見(jiàn)的先天性致殘性疾病，全球約有1000名患者，其臨床表現(xiàn)為病人的骨骼肌和軟結(jié)締組織會(huì)慢慢骨化而導(dǎo)致身體變得僵硬，目前還沒(méi)有有效治療方法。
　　哈佛醫(yī)學(xué)院和波士頓貝斯以色列女執(zhí)事醫(yī)療中心的醫(yī)學(xué)指導(dǎo)員戴米恩·美第奇發(fā)現(xiàn)，與普通骨骼組織不同的是，F(xiàn)OP病人體內(nèi)病態(tài)的軟骨和骨頭細(xì)胞中包含有內(nèi)皮細(xì)胞的生物標(biāo)記。這讓他產(chǎn)生了一個(gè)疑問(wèn)，病人的軟骨和骨頭是否起源于內(nèi)皮細(xì)胞呢？美第奇和同事將引發(fā)FOP的變異基因轉(zhuǎn)變?yōu)榱苏５膬?nèi)皮細(xì)胞。令人意想不到的是，內(nèi)皮細(xì)胞接著轉(zhuǎn)化為了一種新的細(xì)胞類型，這種細(xì)胞能夠分裂為骨頭、軟骨、肌肉、脂肪甚至神經(jīng)細(xì)胞的成人干細(xì)胞或骨髓間充質(zhì)干細(xì)胞。進(jìn)一步的實(shí)驗(yàn)發(fā)現(xiàn)，不通過(guò)變異的基因來(lái)誘導(dǎo)這種轉(zhuǎn)變，研究人員也能夠使用兩種特定的蛋白質(zhì)（生長(zhǎng)因子TGF-beta2和BMP4）中的任何一種來(lái)培養(yǎng)內(nèi)皮細(xì)胞，這些蛋白質(zhì)的細(xì)胞交互作用模仿了變異基因的作用，這給科學(xué)家提供了一種更有效的重組細(xì)胞的方法。之后，研究人員將這些重組的細(xì)胞分別放入培養(yǎng)皿中和動(dòng)物身上，它們最終發(fā)育成了一組相關(guān)的組織類型。
　　美第奇表示，這些新的細(xì)胞同骨髓間充質(zhì)干細(xì)胞并不完全一樣，厘清這點(diǎn)非常重要，但它們都具備類似于骨髓間充質(zhì)干細(xì)胞的潛力和可塑性。奧爾森稱，這套系統(tǒng)的強(qiáng)大性在于，這只是一個(gè)自然過(guò)程的重復(fù)，從這個(gè)意義上來(lái)說(shuō)，與目前其他對(duì)細(xì)胞進(jìn)行重組的方法相比，其人工干預(yù)更少。全球FOP領(lǐng)域的專家、賓夕法尼亞州大學(xué)醫(yī)學(xué)院的整形外科分子醫(yī)學(xué)教授弗雷德里克·卡普蘭也是該研究的合作者，他表示，新發(fā)現(xiàn)讓人們首次知道如何利用這個(gè)過(guò)程來(lái)制造病人急需的額外骨骼。美第奇和奧爾森回應(yīng)稱，這些發(fā)現(xiàn)最直接的應(yīng)用將是組織工程學(xué)和個(gè)性化醫(yī)療領(lǐng)域?？茖W(xué)家相信，某一天，接受移植的病人可能會(huì)提取出自己的內(nèi)皮細(xì)胞，然后進(jìn)行重組，接著就可以長(zhǎng)成他們需要的組織類型來(lái)用于移植，并且不會(huì)出現(xiàn)排斥反應(yīng)。(來(lái)源：科技日?qǐng)?bào) 發(fā)布時(shí)間：2010-11-24 13:30:59)

【點(diǎn)評(píng)】
　　該項(xiàng)研究提供了一種非基因重組方式體外培育內(nèi)皮細(xì)胞轉(zhuǎn)化為干細(xì)胞，因?yàn)闇p少了人為干預(yù)，能為細(xì)胞移植提供更好的細(xì)胞源。如果此類干細(xì)胞培育技術(shù)可以像原位再生醫(yī)學(xué)一樣在活體上安全有效地實(shí)現(xiàn)，就可以避免細(xì)胞移植及其副作用。

【原文摘錄】Nature Medicine (2010) doi:10.1038/nm.2252
Conversion of vascular endothelial cells into multipotent stem-like cells
Damian Medici, Eileen M Shore, Vitali Y Lounev, et al.
Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor–dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell–like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.

2. 脂肪組織可生成免疫細(xì)胞
【摘要】
　　法國(guó)國(guó)家科研中心11月22日發(fā)表公報(bào)稱，該機(jī)構(gòu)的研究人員日前發(fā)現(xiàn)，老鼠的脂肪組織能夠生成對(duì)抗過(guò)敏和發(fā)炎的免疫細(xì)胞，這一研究成果顛覆了科學(xué)界以前的觀點(diǎn)，有助于新藥的研制。公報(bào)稱，脂肪組織不僅是油脂的“儲(chǔ)存庫(kù)”，它在生物新陳代謝過(guò)程中也發(fā)揮著重要作用，例如白色脂肪組織中就含有血液中的巨噬細(xì)胞和淋巴細(xì)胞，這些造血細(xì)胞在白色脂肪組織中約占20%。此前人們一直認(rèn)為，這些造血細(xì)胞只能來(lái)自骨髓，是從造血干細(xì)胞中分離出來(lái)的。不過(guò)國(guó)家科研中心的研究人員卻得出了不同的結(jié)論，他們通過(guò)實(shí)驗(yàn)發(fā)現(xiàn)，老鼠的脂肪組織本身就能夠生成造血干細(xì)胞，后者除了分化出造血細(xì)胞，還會(huì)分化出肥大細(xì)胞。肥大細(xì)胞是一種免疫細(xì)胞，在肌體抗擊過(guò)敏和發(fā)炎中發(fā)揮著至關(guān)重要的作用。
　　研究人員表示，肥大細(xì)胞在免疫系統(tǒng)中無(wú)處不在，其作用遠(yuǎn)比人們想象的要大，而脂肪組織通常占到一個(gè)成人體重的10%到50%，如果他們能夠進(jìn)一步證明，人體的脂肪組織也能生成肥大細(xì)胞，那么將給造血和免疫系統(tǒng)疾病患者帶來(lái)希望。該研究成果已經(jīng)發(fā)表在最新一期的美國(guó)《干細(xì)胞》雜志上。（來(lái)源：新華社 李學(xué)梅）

【點(diǎn)評(píng)】
　　這一發(fā)現(xiàn)進(jìn)一步將脂肪組織和免疫系統(tǒng)緊密聯(lián)系在一起。同時(shí)也進(jìn)一步證明脂肪組織能儲(chǔ)存和生產(chǎn)干細(xì)胞。

【原文摘錄】STEM CELLS 2010;28:2065–2072
Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors
Sandrine Poglio, Fabienne De Toni-Costes, Emmanuelle Arnaud, et al.
White adipose tissue (WAT) is a heterogeneous tissue, found in various locations throughout the body, containing mature adipocytes and the stroma-vascular fraction (SVF). The SVF includes a large proportion of immune hematopoietic cells, among which, mast cells that contribute to diet-induced obesity. In this study, we asked whether mast cells present in mice adipose tissue could derive from hematopoietic stem/progenitor cells (HSPC) identified in the tissue. We therefore performed both in vitro and in vivo experiments dedicated to monitoring the progeny of WAT-derived HSPC. The entire study was conducted in parallel with bone marrow-derived cells, considered the gold standard for hematopoietic-lineage studies. Here, we demonstrate that adipose-derived HSPC contain a precursor-cell population committed to the mast cell lineage, and able to efficiently home to peripheral organs such as intestine and skin, where it acquires properties of functional tissue mast cells. Additionally, WAT contains a significant mast cell progenitor population, suggesting that the entire mast cell lineage process take place in WAT. Considering the quantitative importance of WAT in the adult organism and the increasing roles recently assigned to mast cells in physiopathology, WAT may represent an important source of mast cells in physiological and pathological situations.

3.  預(yù)設(shè)基因線路可指示人體細(xì)胞按需分化

【摘要】
　　據(jù)《自然》網(wǎng)站11月25日?qǐng)?bào)道，美國(guó)生物學(xué)家研究出一種基因線路，可以按照需要編制程序，指示細(xì)胞對(duì)想要的信號(hào)作出響應(yīng)。這項(xiàng)技術(shù)有著廣泛用途，比如誘導(dǎo)干細(xì)胞分化成體內(nèi)的不同組織，或在營(yíng)養(yǎng)不良時(shí)激活植物的防御機(jī)制等。相關(guān)研究發(fā)表在11月26日出版的《科學(xué)》雜志上。“從廣泛意義上講，就是對(duì)細(xì)胞的行為和決策進(jìn)行控制，讓其對(duì)任何感興趣的蛋白質(zhì)作出反應(yīng)?！必?fù)責(zé)該項(xiàng)研究的加利福尼亞斯坦福大學(xué)生物工程師克里斯蒂娜·斯莫克說(shuō)，其主要難點(diǎn)在于如何控制細(xì)胞行為，以及如何開(kāi)發(fā)細(xì)胞路徑。
　　為此，研究小組制造了一段DNA（脫氧核糖核酸）作為基因線路，將其插入細(xì)胞轉(zhuǎn)錄到RNA（核糖核酸）中后，它會(huì)去探尋細(xì)胞內(nèi)部是否存在某種特殊的目標(biāo)蛋白質(zhì)，一旦找到，線路就會(huì)給這種蛋白質(zhì)編碼。比如，其中一種線路包含了一種酶的基因，這種酶能讓細(xì)胞對(duì)抗病毒藥物更昔洛韋（ganciclovir）更加敏感。研究人員在基因序列中插入一個(gè)停止信號(hào)，以防止細(xì)胞通過(guò)信使RNA生成工作蛋白質(zhì)，而到下一個(gè)停止信號(hào)時(shí)，它們會(huì)編碼一小段RNA作為一個(gè)適配子，識(shí)別一種叫做beta-聯(lián)蛋白的信號(hào)蛋白質(zhì)（在某些腫瘤中beta-聯(lián)蛋白會(huì)被過(guò)度復(fù)制），找到目標(biāo)后適配子就會(huì)與其結(jié)合，由此會(huì)讓細(xì)胞與信使DNA以某種方式鉸接，從而清除停止信號(hào)以產(chǎn)生酶。為了檢驗(yàn)設(shè)計(jì)線路的效果，他們激活人體細(xì)胞產(chǎn)生額外的beta-聯(lián)蛋白，讓它們變得像癌細(xì)胞，然后用更昔洛韋來(lái)治療，結(jié)果顯示，含有編制線路的細(xì)胞都被藥物殺死了。
　　斯莫克說(shuō)，一條線路里有多個(gè)適配子感受器，能對(duì)不同類型的蛋白質(zhì)起不同的反應(yīng)。從理論上，這種線路能包含任何基因，也可以設(shè)計(jì)適配子來(lái)識(shí)別任何蛋白質(zhì)。通過(guò)扭轉(zhuǎn)這種線路里的“線”，能讓細(xì)胞不僅對(duì)存在的蛋白質(zhì)發(fā)生響應(yīng)，還能對(duì)缺失的蛋白質(zhì)發(fā)生響應(yīng)。加利福尼亞勞倫斯·伯克利國(guó)家實(shí)驗(yàn)室的系統(tǒng)與合成生物學(xué)家亞當(dāng)·阿金說(shuō)，新技術(shù)在靈活性上是一種突破。在利用細(xì)胞信號(hào)方面，其他研究?jī)A向于作為一種“一次性的預(yù)設(shè)工程”（one-offs of bespoke engineering），而斯莫克的線路可以用在不同類型的細(xì)胞中，開(kāi)發(fā)更為廣泛的生物路徑。斯莫克認(rèn)為，這種“細(xì)胞黑客”線路（Cell-hacking circuit）要進(jìn)入臨床應(yīng)用還需再等幾年，但與其他實(shí)驗(yàn)性治療相結(jié)合，他們最終將能夠控制其在體內(nèi)發(fā)揮作用時(shí)的位置和時(shí)機(jī)。比如，通過(guò)指示多功能干細(xì)胞對(duì)體內(nèi)的蛋白質(zhì)蹤跡信號(hào)發(fā)生響應(yīng)，讓它們生出多種組織，分化成希望的樣子；或讓含有特定線路的殺癌免疫細(xì)胞能免受健康細(xì)胞的攻擊。來(lái)源：科技日?qǐng)?bào) 發(fā)布時(shí)間：2010-11-27 9:40:28

【點(diǎn)評(píng)】
　　對(duì)細(xì)胞的行為和決策進(jìn)行控制，這是明顯的人為干預(yù)企圖，如果無(wú)法確保這種干預(yù)只是出現(xiàn)在正確的時(shí)間、地點(diǎn)和事件上，那么它的存在只會(huì)擾亂細(xì)胞正常的生理代謝。

【原文摘錄】Science 2010: Vol. 330 no. 6008 pp. 1251-1255 DOI: 10.1126/science.1192128
Reprogramming Cellular Behavior with RNA Controllers Responsive to Endogenous Proteins
Stephanie J. Culler1, Kevin G. Hoff1 and Christina D. Smolke
Synthetic genetic devices that interface with native cellular pathways can be used to change natural networks to implement new forms of control and behavior. The engineering of gene networks has been limited by an inability to interface with native components. We describe a class of RNA control devices that overcome these limitations by coupling increased abundance of particular proteins to targeted gene expression events through the regulation of alternative RNA splicing. We engineered RNA devices that detect signaling through the nuclear factor κB and Wnt signaling pathways in human cells and rewire these pathways to produce new behaviors, thereby linking disease markers to noninvasive sensing and reprogrammed cellular fates. Our work provides a genetic platform that can build programmable sensing-actuation devices enabling autonomous control over cellular behavior.

4. 無(wú)需動(dòng)物實(shí)驗(yàn)即可快速篩選抗癌藥物

【摘要】科技日?qǐng)?bào) 2010-11-23 10:15:12
　　美國(guó)斯坦福大學(xué)醫(yī)學(xué)院首次成功地在組織培養(yǎng)皿中將人體正常細(xì)胞轉(zhuǎn)變成三維癌細(xì)胞組織。該研究成果提供了觀察細(xì)胞如何分裂和侵入周圍組織的全新途徑，有助于更好地認(rèn)識(shí)癌癥在人體內(nèi)的行為，同時(shí)可望在無(wú)需動(dòng)物實(shí)驗(yàn)的情況下進(jìn)行快速和廉價(jià)的抗癌藥物測(cè)試。研究成果發(fā)表在21日出版的《自然·醫(yī)學(xué)》雜志網(wǎng)絡(luò)版上。
　　斯坦福大學(xué)醫(yī)學(xué)院皮膚科主任保羅·卡瓦里博士表示，利用動(dòng)物模式，上述實(shí)驗(yàn)通常需要數(shù)月的時(shí)間才能完成，而現(xiàn)在只需數(shù)天。據(jù)悉，研究人員的研究重點(diǎn)是上皮細(xì)胞，而上皮細(xì)胞癌癥大約占人類癌癥發(fā)病率的90%。研究人員使用的人體正常細(xì)胞取自皮膚、宮頸、食道和咽喉。為讓正常細(xì)胞發(fā)生癌變，他們首先用病毒去影響可導(dǎo)致細(xì)胞失控生長(zhǎng)的兩個(gè)已知基因通道，并發(fā)現(xiàn)同時(shí)更改這兩個(gè)基因通道是令正常細(xì)胞轉(zhuǎn)化的有效途徑。然后，研究人員將出現(xiàn)初期癌變的上皮細(xì)胞植入裝有人體其他皮膚成分的組織培養(yǎng)皿中。觀察結(jié)果顯示，上皮細(xì)胞首先附著在培養(yǎng)皿內(nèi)的基膜上，并形成了看上去是正常的三維橫截面皮膚；然而在大約6天后，細(xì)胞開(kāi)始出現(xiàn)惡兆性變化，它們穿透了基膜，并侵入下面的基質(zhì)組織中?？ㄍ呃镎f(shuō)：“這反映的是人體腫瘤所發(fā)生的自然現(xiàn)象。通常，細(xì)胞從早期惡性狀態(tài)變?yōu)榍秩胄园┌Y需要數(shù)年的時(shí)間。只有在這種完好的人體組織模型環(huán)境下，細(xì)胞變化才會(huì)發(fā)展得更快?！贝送?，在對(duì)培養(yǎng)出的癌癥細(xì)胞進(jìn)行分析后，研究人員發(fā)現(xiàn)其形狀與人體內(nèi)自然生長(zhǎng)的癌細(xì)胞相符。利用新開(kāi)發(fā)的癌細(xì)胞組織培養(yǎng)皿，研究人員對(duì)20種實(shí)驗(yàn)性抗癌藥物進(jìn)行了測(cè)試，并追蹤到3種實(shí)驗(yàn)藥物能夠讓上皮細(xì)胞停止侵入基膜，顯示出它們可成為潛在的候選藥物。雖然候選藥物能否最終開(kāi)發(fā)成抗癌藥物還需要進(jìn)行優(yōu)化后用于動(dòng)物實(shí)驗(yàn)，但是利用癌細(xì)胞組織培養(yǎng)皿進(jìn)行先期篩選的手段可以讓研究人員縮小選擇范圍。要強(qiáng)調(diào)的是，上述20種抗癌藥物中大多數(shù)本身不易在動(dòng)物體進(jìn)行測(cè)試，其原因在于，以它們目前的形態(tài)還存在難以管理和毒性等問(wèn)題。
　　三維癌細(xì)胞培養(yǎng)環(huán)境還顯示，基質(zhì)細(xì)胞本身以某種方式促進(jìn)了癌變上皮細(xì)胞的侵入，這些細(xì)胞并不需要急劇分裂而達(dá)到侵入基膜的目的。卡瓦里表示，他們現(xiàn)在能夠從不同的人體組織培養(yǎng)出多種腫瘤，獲得了可能反映人體腫瘤自然產(chǎn)生現(xiàn)象的新途徑。然而他同時(shí)指出，新的研究模式?jīng)]有包含人體其他的生物因素，如免疫系統(tǒng)和新陳代謝。

【點(diǎn)評(píng)】
　　利用這一人工癌變模型，在組織培養(yǎng)皿中進(jìn)行先期篩選，的確可以縮小那些不易處理的候選藥物的范圍，只是可靠性還有待驗(yàn)證。另一方面，現(xiàn)在的科學(xué)對(duì)于將正常細(xì)胞變成癌細(xì)胞是越來(lái)越有辦法了，但是對(duì)于如何將癌細(xì)胞變成正常細(xì)胞還是一籌莫展。

【原文摘錄】Nature Medicine (21 November 2010) doi:10.1038/nm.2265
Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia
Todd W Ridky, Jennifer M Chow, David J Wong, Paul A Khavari
Refined cancer models are required if researchers are to assess the burgeoning number of potential targets for cancer therapeutics in a clinically relevant context that allows a fast turnaround. Here we use tumor-associated genetic pathways to transform primary human epithelial cells from the epidermis, oropharynx, esophagus and cervix into genetically defined tumors in a human three-dimensional (3D) tissue environment that incorporates cell-populated stroma and intact basement membrane. These engineered organotypic tissues recapitulated natural features of tumor progression, including epithelial invasion through basement membrane, a complex process that is necessary for biological malignancy in 90% of human cancers. Invasion was rapid and was potentiated by stromal cells. Oncogenic signals in 3D tissue, but not 2D culture, resembled gene expression profiles from spontaneous human cancers. We screened 3D organotypic neoplasia with well-characterized signaling pathway inhibitors to distill a clinically faithful cancer gene signature. Multitissue 3D human tissue cancer models may provide an efficient and relevant complement to current approaches to characterizing cancer progression.

5. 恢復(fù)p53功能為主的腫瘤療法的局限性

【摘要】Nature 2010-11-25 17:37:09
　　p53 腫瘤抑制通道的失活是人類癌癥的一個(gè)普遍特征，所以人們便想，恢復(fù)已形成的腫瘤中的p53 功能也許會(huì)是一種有效療法。然而，本期Nature上兩篇論文突顯了以p53為方向的癌癥療法在實(shí)踐上的局限性。他們?cè)谝粋€(gè)K-Ras-driven肺癌模型中發(fā)現(xiàn)，由p53調(diào)控的腫瘤抑制只在腫瘤發(fā)展的后期階段才發(fā)揮作用，這個(gè)時(shí)候K-Ras致癌信號(hào)已達(dá)到足以激活A(yù)RF-p53通道的閾限。這意味著p53的重新表達(dá)未能抑制腫瘤發(fā)生的早期階段，盡管它的確誘導(dǎo)了更為激進(jìn)的腫瘤的退行。

【點(diǎn)評(píng)】
　　p53的重新表達(dá)不能抑制早期腫瘤的發(fā)生，癌變的產(chǎn)生是多因素事件，在細(xì)胞活動(dòng)的整體網(wǎng)絡(luò)里，單一因素只能起到部分作用，它依然受其他因素影響。

【原文摘錄】Nature 468, 567-571 (24 November 2010) doi:10.1038/nature09526
Selective activation of p53-mediated tumour suppression in high-grade tumours
Melissa R. Junttila, Anthony N. Karnezis, Daniel Garcia, et al.
Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53, it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19ARF. Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

6. 蛋白酶體助生殖細(xì)胞“返老還童”
【摘要】
　　“返老還童”在自然界真的存在嗎？法國(guó)里昂的科學(xué)家在線蟲(chóng)生殖過(guò)程中首次發(fā)現(xiàn)卵母細(xì)胞在受精前的某一刻“返老還童”。首先，他們發(fā)現(xiàn)生殖細(xì)胞也會(huì)變老，積累羰基化和氧化的損傷蛋白，更主要的是，他們觀察到在卵母細(xì)胞成熟的某一精確時(shí)刻，蛋白氧化水平會(huì)突然降低，這是由于蛋白酶體對(duì)損傷蛋白進(jìn)行了“清洗”，使其“返老還童”。

【點(diǎn)評(píng)】
　　生殖細(xì)胞的“返老還童”避免將老化信息遺傳下去，而這種機(jī)制如果也存在于組織細(xì)胞里，并且能夠被激活，那么也有可能實(shí)現(xiàn)成熟個(gè)體的年輕化。

【原文摘錄】Aging Cell, 2010; 9 (6): 991 DOI: 10.1111/j.1474-9726.2010.00625.x
Carbonylated proteins are eliminated during reproduction in C. elegans.
Jérôme Goudeau, Hugo Aguilaniu.
Oxidatively damaged proteins accumulate with age in many species. This means that damage must be reset at the time of reproduction. To visualize this resetting in the roundworm Caenorhabditis elegans, a novel immunofluorescence technique that allows the detection of carbonylated proteins in situ was developed. The application of this technique revealed that carbonylated proteins are eliminated during C. elegans reproduction. This purging occurs abruptly within the germline at the time of oocyte maturation. Surprisingly, the germline was markedly more oxidized than the surrounding somatic tissues. Because distinct mechanisms have been proposed to explain damage elimination in yeast and mice, possible common mechanisms between worms and one of these systems were tested. The results show that, unlike in yeast, the elimination of carbonylated proteins in worms does not require the presence of the longevity-ensuring gene, SIR-2.1. However, similar to findings in mice, proteasome activity in the germline is required for the resetting of carbonylated proteins during reproduction in C. elegans. Thus, oxidatively damaged proteins are eliminated during reproduction in worms through the proteasome. This finding suggests that the resetting of damaged proteins during reproduction is conserved, therefore validating the use of C. elegans as a model to study the molecular basis of damage elimination.