Versatile functions of LANA in KSHV pathogenesis

LANA 在 KSHV 发病机制中的多功​​能功能

• 批准号: 9240595
• 负责人: Ke Lan
• 金额: $ 10.34万
• 依托单位: INSTITUT PASTEUR OF SHANGHAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240595
• 关键词: Academy; Acquired Immunodeficiency Syndrome; Affinity Chromatography; Antigen Targeting; Binding Proteins; Cell Nucleus; Cell Proliferation; Cells; China; Chinese People; Common Neoplasm; Communicable Diseases; Complex; Developing Countries; Disease; Embryonic Development; Epigenetic Process; Episome; Etiology; Gene Expression; Gene Targeting; Genes; Genetic; Genome; Goals; HIV; HIV Infections; Health; Histone Deacetylase; Human; Human Herpesvirus 8; In Vitro; Incidence; International; Kaposi Sarcoma; Lesion; Malignant Neoplasms; Mesenchymal; Modeling; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Population; Process; Promoter Regions; Proteins; Rattus; Recruitment Activity; Research; Research Personnel; Role; Science; Signal Pathway; Signal Transduction; Technology; Therapeutic; Transcription Repressor/Corepressor; Transcriptional Regulation; Tumor Angiogenesis; Tumorigenicity; Viral; Viral Proteins; Virus Latency; angiogenesis; cell transformation; gene repression; genetic signature; helix-loop-helix protein differentiation inhibitor; histone methyltransferase; in vivo; inhibitor/antagonist; insight; latency-associated nuclear antigen; latent infection; metaplastic cell transformation; neoplastic cell; new therapeutic target; novel; precursor cell; promoter; public health relevance; response; targeted treatment; therapeutic target; therapy development; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): This application by investigators at the Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, P.R. China, is submitted in response to PAR-14-080 'International Research in Infectious Diseases, including AIDS (R01)'. Along with HIV infection, KSHV and KS have emerged as an important health problem worldwide. The increase in incidence of KSHV-associated tumors in the HIV population is of international concern especially in under-developed countries, such as China. Studies towards the elucidation of the mechanism for KSHV-induced tumorigenesis will provide new therapeutic targets. In KS lesions, the majority of tumor cells are latently infected by KSHV and express viral proteins such as latency associated nuclear antigen (LANA), suggesting an essential role for viral latent infection in tumorigenesis. Using tandem affinity purification (TAP) technology, we identified Krüppel associated box domain associated protein-1 (KAP1) as a novel LANA-binding protein. KAP1 functions as a transcriptional repressor and can change epigenetic state by recruiting histone deacetylase and methyltransferase complex. We previously showed that LANA recruited KAP1 to the RTA promoter region of the KSHV genome, which was involved in transcriptional repression of RTA by LANA. Since KAP1 is an important transcription corepressor, we hypothesize that LANA is capable of regulating global host gene expression through interaction with KAP1. In this project, we will determine whether and how LANA contributes to the pro-proliferative gene signature of KSHV infected cell by down-regulating expression of cellular tumor repressor genes. On the other hand, our previous studies showed that LANA up-regulated BMP-Smad1-Id signaling through sustained BMP-activated p-Smad1 in the nucleus and enhanced its loading on the promoter of BMP target gene Id. We showed that Id proteins were significantly up-regulated in KSHV transformed KMM cells and abundantly expressed in human KS lesions. Strikingly, genetic inhibition of the BMP-Smad1-Id pathway significantly blocked the oncogenic phenotype of KSHV-transformed cells in vitro and in vivo. Interestingly, Id proteins also play critical roles in angiogenesis both during embryogenesis and tumor formation. Thus, we proposed to determine whether LANA modulates BMP-Smad1-Id signaling to facilitate tumor angiogenesis, since abundant angiogenesis is the feature of KS and is the key factor for KS progress. Moreover, we will also determine how LANA regulates the termination process of BMP-induced p-Smad1 activation and the mechanisms by which of Id proteins contribute to angiogenic phenotype of KMM cells. Finally, we will use various BMP signaling inhibitors to evaluate their inhibition efficacy on the tumorigenicity and pro-angiogenic phenotype of KMM cells. Through our studies, we expect to reveal novel insights onto the versatile functions of LANA in KSHV-related malignancies.

 描述（由申请人提供）：本申请由中国科学院上海巴斯德研究所的研究人员提交，以响应 PAR-14-080“国际传染病研究，包括艾滋病 (R01)”与 HIV 感染一起，KSHV 和 KS 已成为世界范围内的一个重要健康问题。HIV 人群中 KSHV 相关肿瘤发病率的增加引起了国际社会的关注，尤其是在艾滋病毒人群中。对中国等不发达国家的研究将提供新的治疗靶点。在KS病变中，大多数肿瘤细胞被KSHV潜伏感染并表达病毒。 诸如潜伏相关核抗原 (LANA) 等蛋白质，表明病毒潜伏感染在肿瘤发生中发挥着重要作用。利用串联亲和纯化 (TAP) 技术，我们将 Krüppel 相关框结构域相关蛋白 1 (KAP1) 鉴定为一种新型 LANA 结合蛋白。 KAP1 发挥转录抑制因子的作用，可以通过招募组蛋白脱乙酰酶和甲基转移酶复合物来改变表观遗传状态，我们之前表明 LANA 将 KAP1 招募到 RTA 启动子区域。 KSHV 基因组参与 LANA 对 RTA 的转录抑制，由于 KAP1 是重要的转录辅阻遏物，因此我们发现 LANA 能够通过与 KAP1 相互作用来调节全局宿主基因表达。 LANA 通过下调细胞肿瘤抑制基因的表达来促进 KSHV 感染细胞的促增殖基因特征。另一方面，我们之前的研究表明 LANA 上调。 BMP-Smad1-Id 信号通过细胞核中持续的 BMP 激活的 p-Smad1 并增强其对 BMP 靶基因 Id 启动子的负载我们发现 Id 蛋白在 KSHV 转化的 KMM 细胞中显着上调，并在人体内大量表达。引人注目的是，BMP-Smad1-Id 通路的基因抑制显着阻断了 KSHV 转化细胞在体外和体内的致癌表型，这表明 Id 蛋白也发挥着关键作用。因此，我们建议确定 LANA 是否调节 BMP-Smad1-Id 信号以促进肿瘤血管生成，因为丰富的血管生成是 KS 的特征，也是 KS 进展的关键因素。 LANA 如何调节 BMP 诱导的 p-Smad1 激活的终止过程以及 Id 蛋白促进 KMM 细胞血管生成表型的机制最后，我们将使用各种 BMP 信号传导。抑制剂评估其对致瘤性和促血管生成的抑制功效 通过我们的研究，我们期望揭示 LANA 在 KSHV 相关恶性肿瘤中的多功能功能的新见解。