Tumor Host Range Mutants of Polyoma and Their Targets

多瘤的肿瘤宿主范围突变体及其靶标

• 批准号: 7880696
• 负责人: THOMAS Livingston BENJAMIN
• 金额: $ 64.62万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880696
• 关键词: Accounting; Affinity Chromatography; Antibodies; Apoptosis; Automobile Driving; Binding; Binding Sites; Biological Assay; C-terminal; Cell physiology; Cells; Chromatin; Co-Immunoprecipitations; Consensus; DNA Footprint; DNA Methylation; Development; Embryonal Carcinoma Cell; Epithelial; Epithelial Cells; Exons; Expression Library; Family; Frequencies; Gel; Gene Targeting; Genetic Transcription; Growth; Human; Hybrids; In Situ; In Vitro; Investigation; Large T Antigen; Libraries; Link; Luciferases; Malignant Neoplasms; Malignant neoplasm of ovary; Methylation; Molecular; Molecular Profiling; Mouse Strains; Mus; Normal Cell; Oligonucleotides; Ovarian; Ovarian Carcinoma; Ovary; Ovulation; Pathway interactions; Pattern; Phage Display; Polyomavirus; Procedures; Promoter Regions; Property; Protein Microchips; Proteins; Radiation; Reporter; Research Personnel; Surface; TP53 gene; Testing; Trans-Activators; Transgenic Mice; Tumor Antigens; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Viral; Viral Tumor Antigens; Virus; Virus Replication; Yeasts; Zinc Fingers; base; cDNA Expression; cell growth; cellular targeting; chromatin immunoprecipitation; cis acting element; in vivo; mouse model; mutant; neoplastic cell; programs; promoter; sialosyl-T antigen; transcription factor; tumor

DESCRIPTION (provided by applicant): We propose to continue to isolate and characterize "tumor host range" (THR) mutants of polyoma virus in efforts to identify and characterize the cellular targets of the viral T (tumor) antigens. The rationale behind this selection is that tumor cells may have undergone the loss of particular function(s) which the wild type virus normally targets. These functions may represent tumor suppressor genes or other regulators of replication and survival which the virus needs to inactivate or alter in some manner in order to replicate efficiently. THR mutants are selected to be able to grow on certain tumor cells but not on normal cells and are presumed to have lost the targeting function. One THR mutants has been used to identify the multi-zinc finger homeotic transcription factor Sal2 as a target of the polyoma large T antigen. We have shown that Sal2 acts in some important respects like p53 in terms of its growth arrest and apoptosis inducing properties. In this application we focus on Sal2 with efforts to determine its downstream cellular gene targets, upstream regulators and protein partners. Expression profiling analysis and chromatin immunoprecipitation (ChIP) will be used in these investigations. We will also seek to determine the mutual effects which large T and Sal2 exert on each other based on their interaction. Sal2 is highly expressed in ovarian surface epithelial cells. Preliminary evidence indicates that Sal2 expression is lost in human ovarian carcinomas. We propose to examine further if such loss occurs and at what frequency in various forms of ovarian carcinoma. We will test the hypothesis that promoter methylation in one of the two alternative Sal2 promoters may account for Sal2 silencing in some cases of ovarian carcinoma. Finally, we will take several approaches to developing a mouse model of ovarian cancer based on recent findings on the large T-Sal2 interaction and on the isolation of a new strain of polyoma which efficiently induces ovarian surface epithelial tumors in certain strains of mice.

描述(由申请人提供)：我们建议继续分离和鉴定多瘤病毒的“肿瘤宿主范围”(Thr)突变体，以努力鉴定和鉴定病毒T(肿瘤)抗原的细胞靶标。这种选择背后的理由是，肿瘤细胞可能已经失去了野生型病毒通常针对的特定功能(S)。这些功能可能代表肿瘤抑制基因或其他复制和存活调节器，病毒需要以某种方式灭活或改变它们，以便有效复制。Thr突变体被选择为能够在某些肿瘤细胞上生长，但不能在正常细胞上生长，并被推测已经失去了靶向功能。一个Thr突变体已被用于鉴定多锌指同源异型转录因子SAL2作为多瘤大T抗原的靶标。我们已经证明，SAL2在一些重要的方面发挥作用，如P53，它具有抑制生长和诱导细胞凋亡的特性。在这项应用中，我们专注于SAL2，努力确定其下游细胞基因靶点、上游调控因子和蛋白质伙伴。在这些研究中将使用表达谱分析和染色质免疫沉淀(CHIP)。我们还将根据它们的相互作用来确定大T和SAL2对彼此的相互影响。SAL2在卵巢表面上皮细胞中高表达。初步证据表明，SAL2在人卵巢癌中表达缺失。我们建议进一步研究在不同形式的卵巢癌中是否发生这种缺失，以及这种缺失的频率是多少。我们将检验这一假设，即两个可供选择的SAL2启动子之一的启动子甲基化可能解释了某些卵巢癌中SAL2沉默的原因。最后，我们将根据最近关于T-SAL2大相互作用的发现和分离出一种新的多瘤株，有效地诱导某些品系的小鼠卵巢表面上皮肿瘤，采用几种方法来建立卵巢癌的小鼠模型。

项目成果

Nek1 and TAZ interact to maintain normal levels of polycystin 2.

• DOI: 10.1681/asn.2010090992
• 发表时间: 2011-05
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: H. Yim;C. Sung;J. You;Yu Tian;T. Benjamin

Shp2 suppresses PyMT-induced transformation in mouse fibroblasts by inhibiting Stat3 activity.

• DOI: 10.1016/j.virol.2010.09.032
• 发表时间: 2011-01-20
• 期刊: Virology
• 影响因子: 3.7
• 作者: Yang Y;Jiang B;Huo Y;Primo L;Dahl JS;Benjamin TL;Luo J
• 通讯作者: Luo J

The polyoma virus large T binding protein p150 is a transcriptional repressor of c-MYC.

• DOI: 10.1371/journal.pone.0046486
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sung CK;Yim H;Gu H;Li D;Andrews E;Duraisamy S;Li C;Drapkin R;Benjamin T
• 通讯作者: Benjamin T

DNA-binding and regulatory properties of the transcription factor and putative tumor suppressor p150(Sal2).

• DOI: 10.1016/j.bbagrm.2011.02.002
• 发表时间: 2011-04
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
• 影响因子: 4.7
• 作者: Gu, Hongcang;Li, Dawei;Sung, Chang K.;Yim, Hyungshin;Troke, Philip;Benjamin, Thomas
• 通讯作者: Benjamin, Thomas

A mouse polyomavirus-encoded microRNA targets the cellular apoptosis pathway through Smad2 inhibition.

• DOI: 10.1016/j.virol.2014.07.052
• 发表时间: 2014-11
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Sung, Chang Kyoo;Yim, Hyungshin;Andrews, Erik;Benjamin, Thomas L.
• 通讯作者: Benjamin, Thomas L.