在11月的《自然·細(xì)胞生物學(xué)》雜志上,，來自美國MCG癌癥研究中心卡皮爾·巴拉教授的實(shí)驗(yàn)室任博士后研究員的楊永華（Yonghua Yang ,音譯，第一作者）發(fā)表的最新研究顯示,，單向環(huán)境壓力（one way environmental stress）是通過降低導(dǎo)致細(xì)胞死亡的一種酶的活性水平來引發(fā)癌癥的,。
楊博士解釋說,，他們發(fā)現(xiàn)壓力誘導(dǎo)因子如氧化應(yīng)激（oxidative stress）能夠召集一種叫做SENP1的蛋白質(zhì)，而這種蛋白能夠從SIRT1酶切割走一種調(diào)節(jié)因子SUMO1,從而降低它的活性,。他還解釋說,，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,。有關(guān)癌癥和壓力關(guān)系的基礎(chǔ)性發(fā)現(xiàn)增加SENP1活性的治療開啟了一扇門,，從而使本該死的細(xì)胞走向死亡。
楊博士表示,，他們想看看是否能阻礙增加癌細(xì)胞存活時(shí)間的過程,，使癌細(xì)胞走向死亡。通常在癌癥中表達(dá)的SIRT1的活性增加,，能使癌細(xì)胞對(duì)化療等抗癌藥物產(chǎn)生更強(qiáng)的抗性,。
楊永華稱，他目前已經(jīng)證實(shí)當(dāng)利用SIRT1進(jìn)行促癌和長壽研究時(shí)擁有不同的目標(biāo),。
研究報(bào)告的另外一名作者兼塞西爾·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）過程。應(yīng)激誘導(dǎo)因子可將SIRT-1酶與SENP1酶關(guān)聯(lián)起來,，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是一種通過一種叫做乙酰化作用的過程影響蛋白質(zhì)功能的調(diào)節(jié)因子,。MCG的研究人員還發(fā)現(xiàn),，SIRT1的蛋白修飾（與SUMO1結(jié)合）使它變得更加活躍，而這一過程需要蛋白修飾基序（能夠促使SUMO1與SIRT1結(jié)合）才能發(fā)生,。
Sirt1(Sirtuin type 1)是依賴于煙酰胺腺嘌呤二核苷酸(NAD+)的組蛋白脫乙酰酶, 為Sirtuins家族成員之一, 與細(xì)胞增殖,、分化,、衰老,、凋亡和代謝密切相關(guān).目前, 有關(guān)Sirt1與衰老和代謝的論文已在Science、Nature、Cell等雜志上連續(xù)刊出.其中, Sirt1通過抑制PPAR?促進(jìn)白色脂肪細(xì)胞中脂肪動(dòng)員, 并且通過下調(diào)肌細(xì)胞標(biāo)志基因表達(dá)來抑制成肌細(xì)胞分化.提示Sirt1不僅是一個(gè)重要的與機(jī)體"長壽"有關(guān)的因子, 而且可能在動(dòng)物脂肪沉積和肌肉發(fā)育中起著關(guān)鍵的調(diào)控作用,。
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.
