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SAG E3 ubiquitin ligase in angiogenesis & carcinogenesis

SAG E3 泛素连接酶在血管生成中的作用

基本信息

批准号：
7894931
负责人：
YI SUN
金额：
$ 29.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894931
关键词：
Abbreviations Angiogenesis Inhibition Apoptosis Biological Biotin Blood Island Blood Vessels Boxing Cancer Model Cell Proliferation Cells Cloning Cullin Proteins DNA Nucleotidylexotransferase Data Embryo Endothelial Cells Endothelial Growth Factors F-Box Proteins Failure Fibroblasts Fluorescence-Activated Cell Sorting Genes Genetic Glioblastoma Goals Growth Human Human Papillomavirus Human papillomavirus 16 Hypoxia Inducible Factor In Situ Nick-End Labeling In Vitro Keratin Knock-out LIF gene Label Modeling Molecular Genetics Mus NF-kappa B Neurofibromatosis 1 Neurofibromatosis Type 1 Protein Neurofibromin 2 Nuclear Phosphotransferases Poly(ADP-ribose) Polymerases Proteins Publishing Radiation Radiation Tolerance Radiosensitization Reactive Oxygen Species Regulation Research Role Skin Carcinogenesis Skin Neoplasms Small Interfering RNA Squamous cell carcinoma Stress TNF gene Teratoma Testing Tetradecanoylphorbol Acetate Transcription Factor AP-1 Transducin Transgenic Model Transgenic Organisms Tumor Necrosis Factor-alpha Tumor Necrosis Factors Umbilical vein Vascular Endothelial Growth Factors Work angiogenesis antiangiogenesis therapy cancer cell cancer therapy carcinogenesis casein kinase II chemical carcinogen chorioallantoic membrane density embryonic stem cell human RBX1 protein in vivo inhibitor/antagonist interest killings knock-down leukemia inhibitory factor novel small molecule stem therapeutic target tumor xenograft tumorigenesis ubiquitin ligase ubiquitin-protein ligase vasculogenesis

项目摘要

SAG (Sensitive to Apoptosis Gone), also known as RBX2IROC2, or RNF7 (RING finger protein 7), is a stress-responsive component of SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligase. Our previous work has shown that SAG promotes cell proliferation and Inhibits apoptosis under stressed conditions. The role of SAG in regulation of angiogenesis and carcinogenesis is, however, largely unknown. Our long-range goal is to achieve cancer therapy through inhibition of angiogenesis and tumorigenesis by targeting SAG. Our strong preliminary data showed that SAG knockout causes mouse embryonic lethality at E1O.5-12.5, largely due to the failure in vasculogenesis and angiogenesis. Embryoid bodies derived from SAG-null embryonic stem (ES) cells are unable to differentiate into endothelial cells to form the interior of blood islands, which is associated with the failure in VEGF induction and in RAS/ERK activation. The teratomas derived from SAG-null ES cells are smaller in size with reduced density of blood vessels and reduced rate of proliferation. We also found that transgenic expression of SAG accelerates the growth of mouse skin tumors induced by chemical carcinogens, whereas SAG knock-down by siRNA inhibits the growth of human cancer cells both in vitro and in vivo. The objectives of this application are 1) to define the role of SAG in angiogenesis and 2) to elucidate its mechanism of action, using mouse ES cells arid human cancer cells. The central hypothesis is that SAG promotes angiogenesis by inducing degradation of 1KB to activate NFKB and degradation of neurofibromin, a NF-1 gene product, to activate RAS. SAG deletion causes the accumulation of 1) lKBa to inactivate NFKB, and 2) neurofibromin to inactivate RAS, resulting in inhibition of angiogenesis. The specific aims to test the hypothesis are 1) to define the role of SAG in regulation of angiogenesis in mouse ES cells and in human cancer cells and 2) to define the mechanism of action by which SAG regulates endothelial differentiation of embryoid bodies. We expect that successful completion of this proposed study will demonstrate that blockade of SAG inhibits angiogenesis through NFKB inactivation by accumulated 1KB and RAS inactivation by accumulated neurofibromin. Targeting SAG in cancer cells, via siRNA silencing or small molecule inhibitors, would, therefore, be a valid antianglogenesis therapy.

SAG又称RBX2IROC2或RNF7，是SCF(Skp1、Cullins、F-box蛋白)E3泛素连接酶的应激反应组分。我们以前的工作表明，在应激条件下，SAG促进细胞增殖并抑制细胞凋亡。然而，SAG在调节血管生成和癌变中的作用在很大程度上是未知的。我们的长期目标是通过靶向SAG抑制血管生成和肿瘤形成来实现癌症治疗。我们强大的初步数据表明，SAG基因敲除导致E10.5-12.5的小鼠胚胎死亡，主要是由于血管生成和血管生成的失败。SAG缺失的胚胎干细胞来源的类胚体不能分化为内皮细胞形成血岛内部，这与血管内皮生长因子诱导失败和RAS/ERK激活失败有关。来自SAG缺失ES细胞的畸胎瘤体积较小，血管密度降低，增殖率降低。我们还发现，SAG的转基因表达加速了化学致癌物诱导的小鼠皮肤肿瘤的生长，而siRNA敲除SAG在体内外都抑制了人癌细胞的生长。这项应用的目的是1)确定SAG在血管生成中的作用，2)利用小鼠ES细胞和人类癌细胞阐明其作用机制。中心假说是SAG通过诱导1KB的降解激活来促进血管生成 NFkB和降解NF-1基因产物神经纤维蛋白来激活RAS。SAG缺失导致1)1KBA的积聚使NFKB失活，2)神经纤维蛋白使RAS失活，从而抑制血管生成。验证这一假说的具体目的是：1)确定SAG在调节小鼠ES细胞和人类癌细胞血管生成中的作用；2)确定SAG调节血管内皮细胞分化的作用机制。类胚体。我们期望这项拟议研究的成功完成将证明阻断SAG通过累积1kb的NFKB失活和累积的神经纤维蛋白失活RAS来抑制血管生成。因此，通过siRNA沉默或小分子抑制剂在癌细胞中靶向SAG将是一种有效的抗血管形成治疗方法。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases.

DOI：
10.1158/1535-7163.mct-10-0643
发表时间：
2011-04
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Yang J;McEachern D;Li W;Davis MA;Li H;Morgan MA;Bai L;Sebolt JT;Sun H;Lawrence TS;Wang S;Sun Y
通讯作者：
Sun Y

Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2.

DOI：
10.1158/0008-5472.can-08-0632
发表时间：
2008-09-15
期刊：
Cancer research
影响因子：
11.2
作者：
Zheng M;Morgan-Lappe SE;Yang J;Bockbrader KM;Pamarthy D;Thomas D;Fesik SW;Sun Y
通讯作者：
Sun Y

ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence.

ROC1/RBX1 E3泛素连接酶沉默通过顺序诱导G2-M停滞，凋亡和衰老来抑制肿瘤细胞的生长。

DOI：
10.1158/0008-5472.can-08-4671
发表时间：
2009-06-15
期刊：
CANCER RESEARCH
影响因子：
11.2
作者：
Jia, Lijun;Soengas, Maria S.;Sun, Yi
通讯作者：
Sun, Yi

Small RING Finger Proteins RBX1 and RBX2 of SCF E3 Ubiquitin Ligases: The Role in Cancer and as Cancer Targets.

DOI：
10.1177/1947601910382776
发表时间：
2010-07
期刊：
Genes & cancer
影响因子：
0
作者：
Wei D;Sun Y
通讯作者：
Sun Y

Cardiac glycosides inhibit p53 synthesis by a mechanism relieved by Src or MAPK inhibition.

DOI：
10.1158/0008-5472.can-09-0891
发表时间：
2009-08-15
期刊：
Cancer research
影响因子：
11.2
作者：
Wang Z;Zheng M;Li Z;Li R;Jia L;Xiong X;Southall N;Wang S;Xia M;Austin CP;Zheng W;Xie Z;Sun Y
通讯作者：
Sun Y