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HIV, HERV-K and Human Cancer

HIV、HERV-K 和人类癌症

基本信息

批准号：
10132254
负责人：
MARIE-LOUISE HAMMARSKJOLD
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132254
关键词：
Address Aggressive course Alternative Splicing Binding Binding Proteins Biological Assay Cancer Etiology Cells Cis-Acting Sequence Development Elements Embryonic Development Endogenous Retroviruses Etiology Family Gene Expression Gene Proteins Genes Germ Cell Cancers Germ cell tumor HIV HIV Infections HIV Seropositivity Human Human Genome Human immunodeficiency virus test Immune System Diseases Individual Inflammation Introns Invaded Lead Malignant Neoplasms Measures Mediating Melanoma Cell Messenger RNA Mutation Normal Cell Oncogenes Oncogenic Oncoproteins Patients Peripheral Blood Mononuclear Cell Play Process Protein Isoforms Proteins Publications Publishing RNA RNA Binding Regulation Reporter Reporting Resources Response Elements Role Seminoma Structure System Testing Tissues Translating Translations Virus base cancer cell cancer risk cancer type design experimental study genetic regulatory protein mRNA Expression melanoma novel programs response rev Genes rev Protein tat Genes transcriptome sequencing tumor tumorigenesis vector

项目摘要

This study will examine the potential role that HIV Rev plays in activating the human endogenous retrovirus family, HERV-K (HML-2) type 2 and cellular genes containing RcREs in HIV-infected individuals, and how this might initiate a program of gene expression leading to oncogenesis. Endogenous retroviruses constitute 8% of the human genome, though many are known to be inactive due to multiple mutations. The HERV-K (HML-2) family were the most recent to invade the human genome and are the most active. Several copies of these viruses retain the capacity for expression of structural as well as regulatory proteins. Many recent studies have indicated that these viruses are active in several different types of human cancer and they also have been shown to be activated during HIV infection. However, a direct role for HERVs in oncogenesis remains unknown, although regulatory proteins expressed by the HERV-K (HML-2) viruses have been proposed to function as oncogenes and as activators of cellular genes in embryogenesis. The HERV-K regulatory protein, Rec, is a protein that binds to Rec Response elements (RcREs) in HERV mRNAs with retained introns to promote their export and expression. This is analogous to the role of Rev and RRE in HIV infection. The proposed experiments will analyze HIV and HERV-K molecular interactions in HIV infection. Specifically, we will explore the hypothesis that HIV Tat and Rev proteins induce the expression of HERV-K from proviral copies, leading to the expression of functional Rec proteins. Rec could then directly interact with cis-acting “RcRE” elements in cellular RNAs to promote their nucleo-cytoplasmic export and expression. It is also possible that Rev may directly interact with cellular genes containing RcREs. These processes could lead to oncogenesis through expression of new protein isoforms. In this proposal, assays will be developed to measure functional Rec expression and to identify cellular RNAs, which contain cis-acting sequences (cellular RcREs),that are directly regulated by Rec or Rev at the posttranscriptional level. Based on the known specific role of Rec and Rev proteins in the regulation of mRNA with retained introns, it is expected that many of the induced mRNAs will represent this type of alternatively spliced RNA and encode novel protein isoforms that may be involved in cancer. The initial focus of these studies will be in two types of human cancer: malignant melanoma and germ cell cancer (seminoma). HERV-K (HML-2) type 2 activation is well established in both of these cancers and they also have been reported to be over-represented in HIV infected individuals. At the conclusion of this study, it is expected that significant novel information about HIVRev interactions with HERV-K and cellular genes will have been generated, and the potential role of these interactions in cancer development further elucidated.

本研究将探讨HIV Rev在激活人类内源性逆转录病毒中的潜在作用 HIV感染者中HERV-K（HML-2）2型和含有RcRE的细胞基因，以及这是如何可能启动一个基因表达程序导致肿瘤发生。内源性逆转录病毒占人类基因组，虽然许多已知是无活性的，由于多个突变。HERV-K（HML-2）家族是最近入侵人类基因组的家族，也是最活跃的家族。几份这个病毒保留了表达结构蛋白和调节蛋白的能力。最近的许多研究表明，这些病毒在几种不同类型的人类癌症中具有活性而且它们也被证明在艾滋病毒感染时被激活。然而，HERV在以下方面的直接作用肿瘤发生仍然未知，尽管HERV-K（HML-2）病毒表达的调节蛋白具有被认为在胚胎发生中起致癌基因和细胞基因激活剂的作用。HERV-K 调节蛋白Rec是一种与HERV mRNA中的Rec应答元件（RcRE）结合的蛋白质，保留内含子以促进其输出和表达。这类似于Rev和RRE在HIV中的作用。感染拟议的实验将分析HIV感染中HIV和HERV-K分子的相互作用。具体而言，我们将探讨HIV达特和Rev蛋白诱导HERV-K表达的假设从前病毒拷贝，导致功能性Rec蛋白的表达。Rec可以直接与细胞RNA中的顺式作用“RcRE”元件，以促进其核质输出和表达。是 Rev也可能与含有RcRE的细胞基因直接相互作用。这些过程可能导致通过表达新的蛋白质异构体来促进肿瘤发生。在这个提议中，将开发检测方法来测量功能性Rec表达并鉴定细胞内的 RNA，含有顺式作用序列（细胞RcRE），在细胞内直接受Rec或Rev调控。转录后水平。基于已知Rec和Rev蛋白在mRNA调节中的特定作用，在保留内含子的情况下，预计许多诱导的mRNA将代表这种类型的替代性表达。剪接RNA并编码可能参与癌症的新蛋白质同种型。这些最初的焦点研究将针对两种人类癌症：恶性黑色素瘤和生殖细胞癌。HERV-K （HML-2）2型活化在这两种癌症中均已确立，并且据报道它们也是在艾滋病毒感染者中比例过高。在这项研究的结论，预计有意义的小说，将产生关于HIVRev与HERV-K和细胞基因相互作用的信息，进一步阐明了这些相互作用在癌症发展中的潜在作用。