Papillomavirus E2 Growth Suppression Mechanisms

乳头瘤病毒 E2 生长抑制机制

• 批准号: 7647591
• 负责人: Peter M Howley
• 金额: $ 57.41万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647591
• 关键词: Affect; Amino Acids; Anogenital cancer; Benign; Bovine Papillomavirus; C-terminal; Cancer cell line; Cell Aging; Cell Line; Cervical; Cervix carcinoma; Characteristics; Chromatin; Chromosomes; Clinical; Complex; DNA; DNA Binding; Dimerization; Epithelial Cells; GAS41 gene; Gene Expression; Genes; Genetic Transcription; Genital system; Genome; Growth; HPV-High Risk; Human; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 18; Human papillomavirus 6; Laboratories; Lead; Length; Lesion; Link; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Mediating; N-terminal; Oncogene Proteins; Oncogenes; Open Reading Frames; Papillomavirus; Papovaviridae; Pathway interactions; Play; Premalignant; Principal Investigator; Proteins; RNA Splicing; Reporter; Repression; Retinoblastoma Protein; Role; Screening procedure; Sequence Homology; Series; Small Interfering RNA; Structure; TP53 gene; Tumor Suppressor Proteins; Variant; Viral; Viral Genome; Western Blotting; Work; base; carcinogenesis; cell growth; design; gene repression; genetic regulatory protein; high throughput screening; histone acetyltransferase; human ZNF45 protein; interest; novel; programs; promoter; protein function; transcription factor; transforming virus; tumor

The human papillomaviruses (HPVs) are associated with human cervical cancer as well as some other anogenital cancers and some upper airway cancers. Over 140 different HPVs have now been identified and a subset of these have been associated with these cancers. HPVs are classified as either 'high risk1 (HPV 16, 18) or 'low risk' (HPV 6, 11), based on the clinical lesions with which they are associated and the likelihood for these lesions to progress to cancer. Approximately 90 percent of human cervical cancers harbor the DNA of a high risk HPV type from which two viral oncoproteins, E6 and E7, are invariably expressed. One characteristic of HPV related carcinogenic progression is the frequent integration of the viral genome into the human chromosome in the cancer cells in a manner that results in the loss of expression of the viral E2 gene and to high levels of E6/E7 gene expression. The loss of E2 expression is an important step in HPV associated carcinogenic progression since E2 is able to repress the E6/E7 promoter. The loss of E2 results in the derepression of E6 and E7 oncogene expression. Indeed the expression of the full length E2 protein in HPV positive cervical carcinoma cell lines results in a growth arrest and cellular senescence. The consequent loss of E6 and E7 results in the stabilization of p53 and pRB that in turn mediate cellular growth suppression. The mechanisms by which different forms of E2 mediate this repression however have not yet been established and thjs project is designed to identify genes and pathways involved in this transcriptional repression. The first aim is designed to identify genes and pathways involved in E2-mediated repression of the E6/E7 promoter utilizing a non-biased whole genome siRNA screen. The second aim will determine the mechanisms involved in the repression of the E6/E7 viral promoter. This will focus on novel transcription factors and chromatin modifiers that are revealed and validated in the screen. A third aim will identify the factors and mechanisms involved repression of HPV gene expression that is mediated by a second spliced form of E2 (known as E8AE2C) that has not been extensively studied. A final aim will explore the biologic relevance of the cellular genes identified in the E2 and E8AE2C repression screens in HPV infected epithelial cells and in human cancers.

人乳头瘤病毒（HPV）与人类宫颈癌以及其他一些有关 肛门癌和一些上呼吸道癌。现在已经确定了140多种不同的HPV，并且 这些子集与这些癌症有关。 HPV被归类为“高风险1”（HPV 16、18）或“低风险”（HPV 6、11），基于与之关联的临床病变 这些病变发展为癌症的可能性。大约90％的人类宫颈癌 藏有高风险HPV类型的DNA，两种病毒癌蛋白E6和E7始终是 表达。 HPV相关的致癌发展的一种特征是病毒的频繁整合 基因组以癌细胞中的人类染色体的形式导致表达丧失的方式 病毒E2基因和高水平的E6/E7基因表达。 E2表达的损失是重要的 由于E2能够抑制E6/E7启动子，因此在HPV相关的致癌过程中步骤。损失 E2导致E6和E7致癌基因表达的压抑。确实是完整的表达 HPV阳性宫颈癌细胞系中的长度E2蛋白会导致生长停滞和细胞 衰老。随之而来的E6和E7的损失导致p53和PRB的稳定，又导致 介导细胞生长抑制。不同形式的E2介导的机制 然而，尚未建立抑制，THJS项目旨在识别基因和 该转录抑制涉及的途径。第一个目的旨在识别基因和 E2介导的E6/E7启动子的抑制涉及的途径利用无偏置的整个基因组 siRNA屏幕。第二个目标将确定抑制E6/E7病毒的机制 发起人。这将着重于揭示的新型转录因子和染色质修饰剂，并 在屏幕中验证。第三个目标将确定涉及抑制HPV基因的因素和机制 由尚未被介导的E2的第二剪接形式（称为E8AE2C）介导的表达 广泛研究。最终目标将探索E2中鉴定的细胞基因的生物学相关性 在HPV感染的上皮细胞和人类癌症中，E8AE2C抑制筛选。