Papillomavirus E2 Growth Suppression Mechanisms

人乳头瘤病毒（HPV）与人宫颈癌以及其他一些疾病有关。 肛门生殖器癌和一些上呼吸道癌。目前已鉴定出140多种不同的HPV， 其中一部分与这些癌症有关。HPV被分类为“高危1型”（HPV 16，18）或“低风险”（HPV 6，11），基于与它们相关的临床病变和 这些病变进展为癌症的可能性。大约90%的人类宫颈癌 携带高风险HPV类型的DNA，其中两种病毒癌蛋白E6和E7总是 表达。HPV相关的致癌进展的一个特征是病毒的频繁整合， 基因组插入癌细胞中的人类染色体中，导致基因组表达丧失 病毒E2基因和高水平的E6/E7基因表达。E2表达的缺失是一个重要的因素， HPV相关致癌进展的一步，因为E2能够抑制E6/E7启动子。损失 E2的表达导致E6和E7癌基因表达的去抑制。事实上， HPV阳性宫颈癌细胞系中长度E2蛋白导致生长停滞和细胞凋亡 衰老随后E6和E7的丢失导致p53和pRB的稳定， 介导细胞生长抑制。不同形式的E2介导这一过程的机制 然而，还没有建立抑制，thjs项目旨在确定基因， 参与这种转录抑制的途径。第一个目标是识别基因， E6/E7启动子的E2介导的抑制中涉及的途径 siRNA筛选。第二个目标是确定E6/E7病毒的抑制机制。 启动子这将集中在新的转录因子和染色质修饰剂，揭示和 在屏幕上验证。第三个目标是确定参与HPV基因抑制的因素和机制 由E2的第二种剪接形式（称为E8 AE 2C）介导的表达，其尚未被表达。 广泛研究。最后一个目标是探索E2中鉴定的细胞基因的生物学相关性。 和E8 AE 2C阻遏筛选。

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.