Small ubiquitin-like modifier 1-3 conjugation [corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival.
Small ubiquitin-like modifier 1-3 conjugation [corrected] is activated in human astrocytic brain tumors and is required for glioblastoma cell survival.
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DOI：
10.1111/cas.12047
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发表时间：
2013-01
期刊：
影响因子：
5.7
通讯作者：
Paschen W
中科院分区：
文献类型：
--
作者：
Yang W;Wang L;Roehn G;Pearlstein RD;Ali-Osman F;Pan H;Goldbrunner R;Krantz M;Harms C;Paschen W
小泛素样修饰物（SUMO 1，2，3）是一组与靶蛋白的赖氨酸残基缀合从而修饰其活性、稳定性和亚细胞定位的蛋白质。大量SUMO靶蛋白是参与基因表达的转录因子和其他核蛋白。此外，SUMO接合在基因组稳定性、新合成蛋白质的质量控制、蛋白质的蛋白酶体降解和DNA损伤修复中起关键作用。因此，预期SUMO结合蛋白水平的任何显著增加对细胞的命运具有重大影响。我们发现SUMO结合在人脑星形细胞肿瘤中被激活。SUMO 1-和SUMO 2/3-结合蛋白的水平在肿瘤样品中显著增加。这种效应在低级别星形细胞瘤（WHO II级）中最不明显，在多形性胶质母细胞瘤（WHO IV级）中最明显。我们还发现Ubc 9的水平显着上升，这是迄今为止发现的唯一SUMO结合酶。通过沉默SUMO 1 -3的表达来阻断SUMO 1 -3在胶质母细胞瘤细胞中的结合，从而阻断了DNA合成、细胞生长和细胞的克隆存活。它还导致H2 AX的DNA-PK依赖性磷酸化，指示DNA双链损伤和G2/M细胞周期停滞。总的来说，这些发现突出了SUMO结合在DNA损伤修复过程中的关键作用，并暗示SUMO结合途径可能是旨在增加胶质母细胞瘤对放射和化疗敏感性的治疗干预的新靶点。
Small ubiquitin-like modifier (SUMO1, 2, 3) is a group of proteins that conjugate to lysine residues of target proteins thereby modifying their activity, stability, and subcellular localization. A large number of SUMO target proteins are transcription factors and other nuclear proteins involved in gene expression. Furthermore, SUMO conjugation plays key roles in genome stability, quality control of newly synthesized proteins, proteasomal degradation of proteins and DNA damage repair. Any marked increase in levels of SUMO-conjugated proteins is therefore expected to have a major impact on the fate of cells. We show here that SUMO conjugation is activated in human astrocytic brain tumors. Levels of both SUMO1- and SUMO2/3-conjugated proteins were markedly increased in tumor samples. The effect was least pronounced in low-grade astrocytoma (WHO Grade II) and most pronounced in glioblastoma multiforme (WHO Grade IV). We also found a marked rise in levels of Ubc9, the only SUMO conjugation enzyme identified so far. Blocking SUMO1-3 conjugation in glioblastoma cells by silencing their expression blocked DNA synthesis, cell growth and clonogenic survival of cells. It also resulted in DNA-PK-dependent phosphorylation of H2AX, indicative of DNA double-strand damage, and G2/M cell cycle arrest. Collectively, these findings highlight the pivotal role of SUMO conjugation in DNA damage repair processes and imply that the SUMO conjugation pathway could be a new target of therapeutic intervention aimed at increasing the sensitivity of glioblastomas to radio- and chemotherapy.
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影响因子：
16
作者：
Chowdhury, Dipanjan;Xu, Xingzhi;Zhong, Xueyan;Ahmed, Fariyal;Zhong, Jianing;Liao, Ji;Dykxhoorn, Derek M.;Weinstock, David M.;Pfeifer, Gerd P.;Lieberman, Judy
通讯作者：
Lieberman, Judy
影响因子：
4.8
作者：
Furuta, T;Takemura, H;Pommier, Y
通讯作者：
Pommier, Y
影响因子：
11.2
作者：
Hui, AM;Wei, Z;Fine, HA
通讯作者：
Fine, HA
DOI：
10.1158/1078-0432.ccr-08-0618
发表时间：
2008-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brantley EC;Nabors LB;Gillespie GY;Choi YH;Palmer CA;Harrison K;Roarty K;Benveniste EN
通讯作者：
Benveniste EN
影响因子：
6.2
作者：
KLEIHUES, P;SOYLEMEZOGLU, F;BURGER, PC
通讯作者：
BURGER, PC