Modulation of Host Cell Apoptotic Responses by HPVE7

HPVE7 对宿主细胞凋亡反应的调节

• 批准号: 7013214
• 负责人: Karl Munger
• 金额: $ 29.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013214
• 关键词: HeLa cells; apoptosis; biological signal transduction; cell transformation; chromatin immunoprecipitation; clinical research; cysteine endopeptidases; enzyme linked immunosorbent assay; flow cytometry; growth factor receptors; host organism interaction; human papillomavirus; human tissue; immunofluorescence technique; immunoprecipitation; intermolecular interaction; oncoproteins; p53 gene /protein; retinoblastoma protein; small interfering RNA; terminal nick end labeling; tumor necrosis factor alpha; virus protein; virus replication

DESCRIPTION (provided by applicant): Small DNA tumor viruses encode proteins that establish and/or maintain a replication competent cellular milieu to permit replication in differentiated, normally growth arrested host cells. Such induction of aberrant cellular and/or viral DNA synthesis in the absence of concurrent environmental mitogen stimulation causes a situation of conflicting growth signals. This triggers a cellular defense mechanism, the "tropic sentinel response" that eliminates such deviant cells from the proliferative pool through cell-type specific abortive processes such as cell death, differentiation or senescence. Indeed, normal diploid fibroblasts that express single nuclear oncogenes such as adenovirus E1A, c-myc, or human papillomavirus (HPV)-16 E7 undergo cell death when their culture medium is deprived of growth factors. To prevent elimination of their host cells during replication, HPVs encode a complementing function, E6 that neutralizes the tropic sentinel response. While highly effective, such a viral replication strategy is a risky proposition for the host cell. Particularly under conditions of dysregulated viral gene expression that can result from integration of the HPV genome into a host chromosome an infected cell is at increased risk to undergo malignant transformation. The HPV E7 oncoprotein contains at least three molecular determinants, the conserved region 1 homology domain and the pRB binding domains as well as a carboxyl terminal domain that each contribute to the induction of aberrant DNA synthesis. The focus of our research is to identify relevant cellular protein complexes that are targeted through each of these E7 sequences (aims 1 & 2), and to determine the cellular signaling circuits that are triggered to mediate the tropic sentinel response (aim 3). These studies may reveal opportunities for therapeutic modalities designed to unmask the dormant tropic sentinel signal in high-risk HPV associated lesions and cancer.

描述（由申请方提供）：小DNA肿瘤病毒编码的蛋白质可建立和/或维持可复制的细胞环境，以允许在分化的、正常生长停滞的宿主细胞中复制。在没有同时发生的环境有丝分裂原刺激的情况下，这种异常细胞和/或病毒DNA合成的诱导引起生长信号冲突的情况。这触发了细胞防御机制，即“热带哨兵反应”，其通过细胞类型特异性流产过程如细胞死亡、分化或衰老从增殖池中消除此类异常细胞。事实上，表达单核癌基因如腺病毒E1 A、c-myc或人乳头瘤病毒（HPV）-16 E7的正常二倍体成纤维细胞在其培养基缺乏生长因子时经历细胞死亡。为了防止在复制过程中消除宿主细胞，HPV编码了一种互补功能，E6，它可以中和嗜性哨兵反应。 虽然非常有效，但这种病毒复制策略对宿主细胞来说是一个危险的提议。特别是在可能由HPV基因组整合到宿主染色体中引起的病毒基因表达失调的条件下，感染的细胞经历恶性转化的风险增加。HPV E7癌蛋白含有至少三个分子决定簇，保守区1同源结构域和pRB结合结构域以及羧基末端结构域，每个结构域都有助于诱导异常DNA合成。我们研究的重点是确定通过这些E7序列中的每一个靶向的相关细胞蛋白质复合物（目的1和2），并确定被触发以介导热带哨兵反应的细胞信号传导回路（目的3）。这些研究可能揭示了设计用于揭示高危HPV相关病变和癌症中休眠的热带哨兵信号的治疗方式的机会。