據(jù)www.physorg.com網(wǎng)站2007年11月5日?qǐng)?bào)道,，研究人員認(rèn)為，單向環(huán)境壓力可通過(guò)減少一種導(dǎo)致細(xì)胞死亡的酶的活性來(lái)引發(fā)癌癥,。在MCG癌癥中心主任卡皮爾·巴拉教授的實(shí)驗(yàn)室任博士后研究員的楊永華稱,，他們發(fā)現(xiàn)，應(yīng)激誘導(dǎo)因子如氧化應(yīng)激會(huì)補(bǔ)充一種稱之為SENP1的蛋白質(zhì),，它可以將SUMO1第器與SIRT1酶分割開來(lái),，從而導(dǎo)致其活性降低。
作為《自然細(xì)胞生物學(xué)》11月版發(fā)表的一篇研究論文的第一作者,，楊永華稱,，這項(xiàng)有關(guān)壓力與癌癥關(guān)系的基礎(chǔ)性發(fā)現(xiàn)將為治療癌癥提供機(jī)會(huì)，即可以通過(guò)增強(qiáng)SENP1的活性,，使那些正在發(fā)生癌變的細(xì)胞更容易死亡。
楊永華稱：“這是使癌細(xì)胞變得很耐久的方法之一,，他們單向生存得很好,。我們想看看是否我們能阻礙那種過(guò)程和使癌細(xì)胞死亡”,。增強(qiáng)常常存在于癌癥中的SIRT1的活性，甚至?xí)拱┘?xì)胞對(duì)抗癌劑如化學(xué)療法產(chǎn)生更大的抗力,。
楊永華稱,，此項(xiàng)研究的復(fù)雜之處在于降低循序漸進(jìn)式的細(xì)胞死亡或細(xì)胞凋亡，而增加其壽命,。然而,，他目前已經(jīng)證實(shí)，當(dāng)利用SIRT1（其長(zhǎng)壽作用的研究仍在進(jìn)行當(dāng)中）進(jìn)行癌癥促進(jìn)和壽命研究時(shí),，它擁有不同的目標(biāo),。癌癥促進(jìn)和壽命研究將為操縱的每一個(gè)細(xì)胞提供不同的目標(biāo)。他稱：“細(xì)胞凋亡的效果是好是壞還取決于不同的情況,。但它對(duì)于癌癥治療是好的,。”
研究報(bào)告的合著者兼塞西爾·F·惠特克以及喬治亞癌癥研究聯(lián)合協(xié)會(huì)著名學(xué)者巴拉稱：“這篇研究文章描述了應(yīng)激如何導(dǎo)致SIRT1的和最終導(dǎo)致癌癥的延遲蛋白修飾和蛋白修飾（desumoylation and sumoylation）過(guò)程。應(yīng)激誘導(dǎo)因子可將SIRT-1酶與SENP1酶關(guān)聯(lián)起來(lái),，因此細(xì)胞變得對(duì)應(yīng)激誘導(dǎo)細(xì)胞凋亡更加有抗力,。一旦SIRT1被延遲修飾，它的活性就會(huì)變低,，而你卻需要它的活性”,。當(dāng)SIRT1的活性降低時(shí)，一種腫瘤抑制基因p53就會(huì)變得更加的活躍,。這種腫瘤抑制基因同樣也能導(dǎo)致細(xì)胞凋亡,。
在全身發(fā)現(xiàn)的SIRT1是一種具有蛋白質(zhì)功能的第器。這種蛋白質(zhì)功能通過(guò)一種被稱之為乙?；倪^(guò)程才能生效,。MCG研究人員還發(fā)現(xiàn)，SIRT1的蛋白修飾（與SUMO1結(jié)合）使它變得更加活躍,，而這一過(guò)程需要蛋白修飾基序（能夠促使SUMO1與SIRT1結(jié)合）才能發(fā)生,。
他們將SUMO1加到人類癌細(xì)胞上增強(qiáng)SIRT1的活性，然后利用SENP1將它分解開來(lái)和減少活性,。正在研究SIRT1長(zhǎng)壽好處的研究人員已在酵母和老鼠體內(nèi)發(fā)現(xiàn)了關(guān)于SIRT1是否有益的相互沖突的實(shí)驗(yàn)信息,。楊永華可能已找到了一種原因：老鼠的SIRT1不包含蛋白修飾基序。當(dāng)他在老鼠體內(nèi)制造出蛋白修飾基序,，SIRT1的活性就會(huì)升高,。楊永華將繼續(xù)從事相關(guān)研究以證實(shí)這些老鼠是否能活得更長(zhǎng)久，但他指出,，相比人類,、酵母或者一種通用的研究模型而言，SIRT1可能對(duì)老鼠有著完全不同的作用。 （中國(guó)科技信息網(wǎng)Chinainfo）
英文原文鏈接參見：http://www.physorg.com/news113502049.html
原始出處:
Nature Cell Biology - 9, 1253 - 1262 (2007)
Published online: 14 October 2007; | doi:10.1038/ncb1645
SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress
Yonghua Yang1, 6, Wei Fu1, Jiandong Chen2, 3, Nancy Olashaw2, 3, Xiaohong Zhang1, 2, 3, Santo V. Nicosia1, 2, 4, Kapil Bhalla5 & Wenlong Bai1, 2, 3
1 Departments of Pathology and Cell Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612–4799, USA.
2 Department of Interdisciplinary Oncology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612–4799, USA.
3 Program of Molecular Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
4 Program of Experimental Therapeutics, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
5 Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912, USA.
6 Current address: Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912, USA.
Correspondence should be addressed to Wenlong Bai [email protected]
SIRT1 is the closest mammalian homologue of yeast SIR2, an important ageing regulator that prolongs lifespan in response to caloric restriction. Despite its importance, the mechanisms that regulate SIRT1 activity are unclear. Our study identifies a novel post-translational modification of SIRT1, namely sumoylation at Lys 734. In vitro sumoylation of SIRT1 increased its deacetylase activity. Conversely, mutation of SIRT1 at Lys 734 or desumoylation by SENP1, a nuclear desumoylase, reduced its deacetylase activity. Stress-inducing agents promoted the association of SIRT1 with SENP1 and cells depleted of SENP1 (but not of SENP1 and SIRT1) were more resistant to stress-induced apoptosis than control cells. We suggest that stress-inducing agents counteract the anti-apoptotic activity of SIRT1 by recruiting SENP1 to SIRT1, which results in the desumoylation and inactivation of SIRT1 and the consequent acetylation and activation of apoptotic proteins.
