P-2: LANA-1 mediated negative regulation of gene expression

P-2：LANA-1 介导的基因表达负调控

• 批准号: 7065940
• 负责人: S DIANE HAYWARD
• 金额: $ 17.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065940
• 关键词: B lymphocyte; CpG islands; DNA binding protein; Kaposi' s sarcoma; cell line; clinical research; exudate /transudate; gene induction /repression; genetic transcription; human herpesvirus 8; human tissue; latent virus infection; lymphoma; methyl group; methylguanine DNA methyltransferase; microcirculation; neoplasm /cancer genetics; neoplastic process; protein protein interaction; transcription factor; vascular endothelium; virus antigen; virus protein; B lymphocyte; CpG islands; DNA binding protein; Kaposi' s sarcoma; cell line; clinical research; exudate /transudate; gene induction /repression; genetic transcription; human herpesvirus 8; human tissue; latent virus infection; lymphoma; methyl group; methylguanine DNA methyltransferase; microcirculation; neoplasm /cancer genetics; neoplastic process; protein protein interaction; transcription factor; vascular endothelium; virus antigen; virus protein

The Kaposi's sarcoma associated herpesvirus, KSHV, is associated with the malignancies Kaposi's sarcoma, primary effusion lymphoma and Castleman's disease. These cancers have an increased incidence in patients with AIDS. The KSHV latency associated nuclear antigen LANA/LANA1 is expressed in all KSHV infected cells and in the associated cancers. LANA is a multi-functional protein that is essential for replication and maintenance of episomal KSHV genomes and also has transcriptional regulatory properties. LANA is known to activate expression of cellular genes through upregulation of E2F and through the Wnt/ beta-catenin pathway. However, when tethered to DNA as a Gal4-fusion, LANA is also capable of repressing transcription and gene array studies also report LANA-mediated transcriptional repression. The ways in which LANA might repress gene expression are not understood nor are the full range of cell gene targets known. Transcriptional silencing is likely to contribute to maintenance of KSHV latency and to the development of KSHV associated malignancies and hence it is proposed to investigate this aspect of LANA's function. The experimental focus will be on genes identified in gene array analyses as being repressed. The contribution to repression of the LANA interacting proteins MeCP2, and sp100-HMG will be evaluated. We have previously demonstrated a role for these proteins in tethering LANA to cell chromosomes and now propose that these proteins might have a dual function in LANA-mediated repression. In addition the contribution of newly identified interactions between LANA and DNA methyl transferases and LANA and transcription factors will be investigated. The individual aims will address: (i) The contribution of histone deacetylases and DNA methyl transferases to the repression of moderately versus strongly repressed promoters, (ii) Investigation of the role of MeCP2 and sp100-HMG in repression, (iii) Examination of transcription factor interactions in LANA mediated repression (iv) Evaluation of LANA-mediated repression in clinical specimens.

Kaposi的肉瘤相关疱疹病毒KSHV与MALIGNANCES KAPOSI的相关 肉瘤，原发性积液淋巴瘤和卡斯特尔氏病。这些癌症的发病率增加 在艾滋病患者中。 KSHV潜伏期相关的核抗原LANA/LANA1在所有KSHV中均表示 感染的细胞和相关的癌症。 LANA是一种多功能蛋白，对于 复制和维持偶发性KSHV基因组，还具有转录调节特性。 已知LANA通过E2F的上调和Wnt/ β-catenin途径。但是，当将DNA作为gal4融合到DNA时，Lana也能够 抑制转录和基因阵列研究还报告了LANA介导的转录抑制。这 LANA可能抑制基因表达的方式不了解，也不是全范围的细胞基因 已知目标。转录沉默可能有助于维持KSHV潜伏期和 开发KSHV相关的恶性肿瘤，因此建议调查Lana的这一方面 功能。 实验重点将放在被抑制基因阵列分析中鉴定出的基因。这 将评估抑制LANA相互作用蛋白MECP2和SP100-HMG的贡献。我们 以前已经证明了这些蛋白质在将拉娜束缚至细胞染色体中的作用，现在 提出这些蛋白质可能在LANA介导的抑制中具有双重功能。另外 LANA和DNA甲基转移酶与LANA之间的新鉴定的相互作用的贡献 转录因子将被研究。个人目标将解决：（i）组蛋白的贡献 脱乙酰基酶和DNA甲基转移酶抑制中等程度与强烈抑制 启动子，（ii）调查MECP2和SP100-HMG在抑制中的作用，（iii）检查 LANA介导的抑制（IV）评估LANA介导的抑制作用中的转录因子相互作用 临床标本。