Anti-pancreatic tumorigenesis by inactivation of SAG/RBX2 E3 ubiquitin ligase

通过灭活 SAG/RBX2 E3 泛素连接酶来抗胰腺肿瘤发生

• 批准号: 8601690
• 负责人: YI SUN
• 金额: $ 16.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601690
• 关键词: Anchorage-Independent Growth; Antineoplastic Agents; Apoptosis; Biological Process; Cancer Patient; Cell Cycle Progression; Cullin Proteins; DNA biosynthesis; Data; Development; F-Box Proteins; Future; Genes; Genetic Transcription; Growth; Health; Human; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Mus; Mutation; Neoplasm Metastasis; Noxae; Nuclear; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Patients; Proteins; Proteomics; Publishing; Role; Signal Transduction; Small Interfering RNA; Testing; Tissues; Transgenic Organisms; Ubiquitination; Validation; Work; cancer therapy; genetic regulatory protein; human FRAP1 protein; in vivo; inhibitor/antagonist; innovation; matrigel; mouse model; novel; outcome forecast; overexpression; pancreatic cancer cells; pancreatic tumorigenesis; tumor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Sensitive to Apoptosis Gene (SAG, human; Sag, mouse) also known as RBX2/ROC2, is an essential RING component of SCF (SKP1, Cullins, F-box proteins) E3 ubiquitin ligase which, by promoting ubiquitination and degradation of various key regulatory proteins, controls several important biological processes including cell cycle progression, signal transduction, transcription, and DNA replication. Our published and unpublished data showed a direct association of SAG with pancreatic cancer as follows: a) SAG is overexpressed in pancreatic cancer tissues, and SAG nuclear expression is associated with poor prognosis of pancreatic cancer patients; b) SAG siRNA knockdown caused accumulation of tumor suppressive proteins and inhibited survival and anchorage-independent growth of pancreatic cancer cells, and c) orthotopic in vivo growth and matrigel invasion of pancreatic cancer cells were significantly inhibited, respectively, by SAG siRNA knockdown. All these studies suggested that SAG overexpression could be oncogenic during pancreatic tumorigenesis. The objectives of this application are to use pancreatic specific Sag transgenic or KO mouse models to mechanistically study the role of Sag in pancreatic tumorigenesis triggered by Kras activation (KrasG12D) and p53 mutation (p53R172H). The central hypothesis is that SAG promotes tumorigenesis by promoting the degradation of tumor suppressive substrates such as DEPTOR, I¿B, and p21/p27, leading to activation of the mTOR and NF¿B pathways. Thus, SAG-pancreatic transgenic expression would promote pancreatic tumorigenesis, initiated by KrasG12D, whereas Sag pancreatic deletion would abrogate oncogenic signals by accumulation of tumor suppressive proteins, thus suppressing pancreatic tumorigenesis triggered by KrasG12D and p53R172H. Two specific aims are proposed to 1) determine the role of Sag in KrasG12D/p53R172H-induced pancreatic tumorigenesis and 2) elucidate mechanism(s) by which Sag regulates pancreatic tumorigenesis. IMPACT: Our study uses mouse models that recapitulate the development of pancreatic ductal adenocarcinoma (PDAC) to investigate the role of Sag E3 ligase in the initiation and progression of PDAC and to elucidate its mechanism of action. Our study will mechanistically validate SAG E3 ubiquitin ligase as a novel anti-pancreatic cancer target and provide proof-of-concept evidence for future discovery of specific inhibitor of SAG E3 ligase as a novel class of anti-pancreatic cancer drugs. Our work is, therefore, highly innovative and of significant impact with translational value.

描述（应用程序提供）：对凋亡基因敏感（SAG，人； SAG，鼠标）也称为RBX2/ROC2，是SCF（SKP1，Cullins，F-box蛋白）E3泛素蛋白连接酶的必不可少的环组成部分，通过促进各种键盘的传播蛋白来控制，该过程是多种键蛋白，该蛋白是泛素蛋白，该蛋白是泛素蛋白的基础。转导，转录和DNA复制。我们发表的未发表的数据显示，SAG与胰腺癌直接相关，如下所示：a）SAG在胰腺癌组织中过表达，而SAG核表达与胰腺癌患者的预后不良有关； b）SAG siRNA敲除引起肿瘤抑制蛋白的积累，并抑制了胰腺癌细胞的生存和锚固非依赖性的生长，c）分别抑制了体内生长和胰腺癌细胞的基质侵入胰腺癌细胞的侵入。所有这些研究表明，在胰腺肿瘤发生过程中，下垂的过表达可能是致癌的。该应用的目标是使用胰腺特异性SAG转基因或KO小鼠模型来机械地研究SAG在KRAS激活（KRASG12D）和p53突变（p53R172H）触发的胰腺肿瘤发生中的作用。假设是，SAG通过促进肿瘤抑制底物（例如Deptor，I i b和P21/P27）的降解来促进肿瘤发生，从而导致MTOR和NFqu途径的激活。这是由KRASG12D发起的垂直转基因表达将促进胰腺肿瘤发生的，而SAG pancreatic pancreatic缺失会通过积累肿瘤抑制性蛋白质来消除致癌信号，从而抑制胰腺肿瘤的胰腺肿瘤，从而触发了Krasg12d和p53r172hr。提出了两个具体的目的是1）确定SAG在KRASG12D/p53r172h诱导的胰腺肿瘤发生的作用和2）SAG调节胰腺肿瘤发生的机制。影响：我们的研究使用小鼠模型来概括胰管导管腺癌（PDAC）的发展来研究SAG E3连接酶在PDAC的主动性和进展中的作用，并阐明其作用机理。我们的研究将机械地将SAG E3泛素连接酶验证为一种新型的抗胰腺癌靶标，并为未来发现SAG E3连接酶特异性抑制剂作为新型抗胰腺癌药物的特定抑制剂提供了概念验证证据。因此，我们的工作具有高度创新性，具有重大影响，并具有翻译价值。