Papillomavirus E2 Growth Suppression Mechanisms

人类乳头瘤病毒(HPV)与人类宫颈癌和其他一些疾病有关 肛门生殖道癌和一些上呼吸道癌。目前已发现140多种不同的HPV， 这些基因中的一部分与这些癌症有关。HPV被归类为高危1(HPV 16，18)或“低风险”(HPV 6，11)，基于与它们相关的临床损害和 这些病变进展为癌症的可能性。大约90%的人类宫颈癌 含有一种高危HPV类型的DNA，其中两种病毒癌蛋白E6和E7总是来自该类型 表达。HPV相关致癌进展的一个特征是病毒的频繁整合 在癌细胞中以一种导致失去表达的方式将基因组插入人类染色体 病毒的E2基因和E6/E7基因的高水平表达。E2表达的丧失是一个重要的 由于E2能够抑制E6/E7启动子，因此参与了HPV相关的致癌进展。损失 抑制E6、E7癌基因的表达。的确，充分的表达了 HPV阳性宫颈癌细胞株中长度为E2的蛋白导致生长停滞和细胞 衰老。随之而来的E6和E7的丢失导致P53和pRb的稳定，进而 调节细胞生长抑制。不同形式的雌二醇调节这一过程的机制 然而，抑制还没有建立起来，这一项目旨在识别基因和 参与这种转录抑制的途径。第一个目标是识别基因和 利用无偏倚全基因组参与E2介导的抑制E6/E7启动子的途径 SiRNA筛选。第二个目标将确定抑制E6/E7病毒的机制 推动者。这将集中在新的转录因子和染色质修饰物，揭示和 已在屏幕上验证。第三个目标是确定与抑制HPV基因有关的因素和机制。 由第二种剪接形式的E2(称为E8AE2C)介导的表达，该剪接形式尚未 经过广泛研究。最终目标将探索在E2中确定的细胞基因的生物学相关性 和E8AE2C抑制筛选在HPV感染的上皮细胞和人类癌症中。

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.